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Text : T cell acute lymphoblastic leukemia (T-ALL) is an invasive hematological malignant disorder of T cell progenitors. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway plays an important role in the development of T-ALL and in the inhibition of the key molecule, JAK2, and could suppress T-ALL cell proliferation. The objective of this study was to investigate the in vitro anti-tumor effects of a novel nilotinib derivative, ND-17, on cancer cell lines via its interactions with JAK2. The effects of ND-17 on cell proliferation and on cell cycle and apoptosis were evaluated using the tetrazolium assay and flow cytometry, respectively. In addition, the ND-17/JAK2 binding interactions were evaluated using surface plasmon resonance and western blot analyses. ND-17 exerted the greatest inhibitory effects on T-ALL cells amongst all hematological cancer cell lines tested. Flow cytometric analysis indicated that ND-17 blocked the cell cycle at the S phase in T-ALL cells. Nilotinib did not significantly inhibit T-ALL cell growth or regulate the cell cycle. Preliminary investigations revealed that the regulation of cyclin-dependent kinases/cyclins was attributed to ND-17-induced cell cycle arrest. Furthermore, ND-17 could bind to JAK2 with strong affinity, and more importantly, ND-17 bound to the ATP pocket of JAK2 in a manner similar to the potent inhibitor. Thus, ND-17 treatment exhibited a prominent effect in inhibiting the phosphorylation of JAK2 in T-ALL cells. An increase in the phosphorylation of JAK2 was observed in interleukin-6- stimulated Jurkat cells, which was reversed by ND-17 treatment. Meanwhile, the combination of TG- 101348 and ND-17 led to further improvement in inhibiting the phosphorylation of JAK2. Moreover, the transfection and knockdown of JAK2 altered the inhibitory effect of ND-17 on Jurkat cell viability. In addition, ND-17 treatment suppressed the JAK/STAT, phosphatidylinositol-3-kinase/protein kinase B/mechanistic target of rapamycin, and mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1 and 2 signaling pathways. These findings suggest that ND-17 could be a promising JAK2 inhibitor for the treatment of T-ALL. | Authentic |
Text : The transforming growth factor β regulator 4 (TBRG4) has been proved to be involved in various types of tumor. However, its contribution in human osteosarcoma (OS) is still unclear. In the present study, immunohistochemistry and quantitative real-time PCR were performed to investigate the expression of TBRG4 in OS tissues obtained from patients and three types of cell lines. The effect of TBRG4 knockdown using lentivirus on tumorigenesis was detected by CCK8, high-content screening analysis, colony formation assay and flow cytometric analysis. Bioinformatics analysis was operated to investigate related signaling pathways following TBRG4 knockdown. The results showed that the expression of TBRG4 increased significantly in OS tissues and MG63 cell line. TBRG4 knockdown inhibited cell proliferation, colony and tumor formation, while activating cell apoptosis. Ingenuity Pathway Analysis and Western blot assay further indicated that TBRG4 knockdown may regulate the proliferation of human MG63 cells through PI3K/Akt signaling pathway. Our results suggest that TBRG4 may become a promising therapeutic target for the treatment of human OS. | Authentic |
Text : Recent studies have demonstrated that microRNAs regulate gene expression and are related to cancer progression. Increasing evidence shows that miR-618 plays an important role in a variety of tumors, including thyroid carcinomas, breast cancer and lymphoma cancer. However, no studies have examined the expression or function of miR-618 in gastric cancer (GC). In this study, we examined the effects and molecular mechanisms of miR-618 in GC. We compared the expression levels of miR-618 in 90 paired GC tissues and adjacent noncancerous tissues. Cell cycle, apoptosis and transwell assays were performed in GC cells with miR-618 mimic or inhibitor in vitro. We first used quantitative PCR(qPCR) to show that miR-618 expression levels were downregulated in GC tissues, which showed statistical significance. Next we used transwell assays to prove that miR-618 suppressed the invasion and migration capacity of GC cells. Furthermore, screening of the miRDB and Target Scan Human databases indicated TGF-β2 as a downstream target of miR-618. In further research, we identified TGF-β2 as a target gene of miR-618 by the luciferase reporter assay. Western blot analysis confirmed that TGF-β2 expression was inversely correlated with miR-618 expression. In situ hybridization showed that miR-618 expression level was downregulated in GC tissues. In conclusion, our findings suggest that miR-618 may function as a tumor suppressor in GC and suppresses metastasis in GC by negatively regulating the transcriptional level of TGF-β2. Anat Rec, 302:931-940, 2019. © 2019 Wiley Periodicals, Inc. | Authentic |
Text : Ovarian cancer (OC) is one of the female malignancies with nearly 45% 5-year survival rate. Circular RNAs (circRNAs), a kind of single-stranded non-coding RNAs, are generated from the back-splicing of cellular housekeeping noncoding RNAs and precursor messenger RNAs. Recent studies revealed that circRNAs have different biological function, including sponging miRNAs, encoding micropeptides, regulating stability of cytoplasmic mRNAs, affecting transcription and splicing, via interacting with DNA, RNA and proteins. Due to their stability, circRNAs have the potential of acting as biomarkers and treatment targets. In this review, we briefly illustrate the biogenesis mechanism and biological function of circRNAs in OC, and make a perspective of circRNAs drug targeting immune responses and signaling pathways in OC. This article can provide a systematic view into the current situation and future of circRNAs in OC. | Authentic |
Text : TNF-α is a central proinflammatory cytokine contributing to malignant tumor progression in tumor microenvironment. In this study, we found the upregulation of miR-105 in colorectal cancer was associated with aggressive phenotype, and the enhanced expression of miR-105 was required for TNF-α-induced epithelial-mesenchymal transition (EMT). The expression of miR-105 was remarkably stimulated by TNF-α in a time-dependent manner using real-time qPCR analysis. Inhibition of miR-105 remarkably weakened the aggressive effects of TNF-α through preventing the activation of NF-κB signaling and the initiation of EMT. Furthermore, miR-105 was demonstrated directly targeted on the 3'-UTRs of RAP2C, a Rap2 subfamily of small GTP-binding protein. Consistently, suppression of RAP2C stimulated the role of miR-105, which dramatically promoted the invasion and metastasis of CRC cells. Thalidomide, a TNF-α and NF-κB inhibitor, significantly weakened the metastasis and homing capacity of miR-105-overexpressed CRC cells in nude mice. Our investigation initiatively illustrated the modulatory role of miR-105 in TNF-α-induced EMT and further CRC metastasis. We also offer a better understanding of TNFα-induced metastasis and suggest an effective therapeutic strategy against CRC metastasis. | Authentic |
Text : Endometrial cancer is the most common gynecological cancer. We identified interleukin 11 (IL11) as a critical mediator of endometrial tumourigenesis and demonstrated that IL11 regulates chondroitin sulfate proteoglycan (CSPG4) in human placental trophoblasts. CSPG4 is a cell membrane protein overexpressed in numerous human cancers, although its role in endometrial cancer has not been investigated. We examined CSPG4 expression and localization in primary human type I endometrioid grade (G) 1-3 tumours by qPCR and immunohistochemistry and determined whether IL11 stimulated CSPG4. IL11 upregulated CSPG4 mRNA in HEC1A (G2-derived endometrial epithelial cancer cell line) cells. IL11 administration to BALB/c nude mice enhanced HEC1A xenograft tumour growth and increased CSPG4 protein in tumours. CSPG4 mRNA was unchanged between human G1-3 endometrial cancer and control tissues. CSPG4 protein levels were elevated in the epithelium of G2 and G3 endometrial cancer and in the tumour-associated stroma of G3 tumour tissues compared to proliferative phase or post-menopausal endometrium. CSPG4 knockdown by siRNA reduced HEC1A proliferation and migration in vitro and reduced gene expression of the key epithelial-to-mesenchymal transition (EMT) regulator SNAIL. Our data suggest that CSPG4 inhibition may impair endometrial cancer progression by reducing cancer cell proliferation, migration and potentially EMT. | Authentic |
Text : Triple-negative breast cancer (TNBC) is the most common and aggressive type of breast cancer with an unfavourable outcome worldwide. Novel therapeutic targets are urgently required to explore this malignancy. This study explored the ceRNA network and the important genes for predicting the therapeutic targets. It identified the differentially expressed genes of mRNAs, lncRNAs and miRNAs between TNBC and non-TNBC samples in four cohorts (TCGA, GSE38959, GSE45827 and GSE65194) to explore the novel therapeutic targets for TNBC. Downstream analyses, including functional enrichment analysis, ceRNA network, protein-protein interaction and survival analysis, were then conducted by bioinformatics analysis. Finally, the potential core protein of the ceRNA network in TNBC was validated by immunohistochemistry. A total of 1,045 lncRNAs and 28 miRNAs were differentially expressed in the TCGA TNBC samples, and the intersections of 282 mRNAs (176 upregulations and 106 downregulations) between the GEO and TCGA databases were identified. A ceRNA network composed of 7 lncRNAs, 62 mRNAs, 12 miRNAs and 244 edges specific to TNBC was established. The functional assay showed dysregulated genes, and GO, DO and KEGG enrichment analysis were performed. Survival analysis showed that mRNA LIFR and lncRNA AC124312.3 were significantly correlated with the overall survival of patients with TNBC in the TCGA databases (P < 0.05). Finally, the LIFR protein was validated, and immunohistochemical results showed the upregulated expression of LIFR in TNBC tissues. Thus, our study presents an enhanced understanding of the ceRNA network in TNBC, where the key gene LIFR may be a new promising potential therapeutic target for patients with TNBC. | Authentic |
Text : Paraoxonase (PON) enzymes possess antioxidant properties and protect against cardiovascular diseases. As a member of PON family, PON3 is primarily synthesized in the liver and poorly investigated. This study aimed to examine the expression of PON3 in human hepatocellular carcinoma (HCC) and investigate the clinical significance and biological function of PON3 in HCC patients. We first analyzed PON3 expression in 50 paired HCC samples (HCC tissues vs matched para-cancerous tissues) and 160 clinical HCC specimens by using immunohistochemistry (IHC). Our results showed that the expression of PON3 was downregulated in HCC and significantly associated with tumor-node-metastasis (TNM) stage, tumor size, and tumor number. Kaplan-Meier survival and Cox regression analyses showed that PON3 was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR). Finally, we aimed to reveal the biological function of PON3 in HCC growth and metastasis, and our results showed that overexpression of PON3 potently inhibited growth and metastasis of HCC. Collectively, our study demonstrated that PON3 exhibited tumor-suppressive effects toward HCC and it might serve as a novel prognostic marker in HCC. | Authentic |
Text : To identify the functioning mode of miR-378 on non-small cell lung cancer (NSCLC) and provide therapeutic targets for NSCLC. Expression levels of miR-378 in human NSCLC tissue samples and NSCLC-derived cell lines were measured by using quantitative Real-time polymerase chain reaction (PCR). Cell proliferation capacity was assessed by methyl thiazolyl tetrazolium (MTT) assay and colony formation assay. Cell apoptosis and cell cycle distribution were identified by flow cytometry. Downstream target gene was confirmed by using luciferase and Western blotting assays. MiR-378 was significantly elevated in NSCLC tissues when compared with para-carcinoma tissues (n=42). Decreased-miR-378 could attenuate cell proliferation capacity, as well as promoted cell apoptosis and induced cell cycle arrest at G0/G1 phase. FOXG1 was chosen as the target gene of miR-378 by bioinformatics analysis and luciferase reporter assay. Moreover, restoration of miR-378 could impair the tumor suppression role of downregulated-miR-378 on NSCLC growth. Decreased-miR-378 exerted tumor-suppressive effects on NSCLC growth via targeting FOXG1 in vitro, which provided an innovative and candidate target for diagnosis and treatment of NSCLC. | Authentic |
Text : Kras mutations are associated with pancreatic ductal adenocarcinoma (PDAC). Although tobacco smoking, pancreatitis, and obesity are known environmental risk factors for PDAC, the contribution of moderate alcohol intake to PDAC remains elusive. In the present study, we tested whether a combination of risk factors or moderate alcohol intake induces PDAC development in mice. Control Pdx1Cre and Pdx1Cre;LSL-KrasG12D mutant mice were fed a Western alcohol diet containing high levels of cholesterol and saturated fat, 3.5% alcohol, and lipopolysaccharide for 5 mo. In addition, mice were treated with cerulein, for induction of pancreatitis, and nicotine every month. Treatment with all of these risk factors promoted development of advanced pancreatic neoplasia and PDAC in the Pdx1Cre;LSL-KrasG12D mice but not in the control Pdx1Cre mice. Moderate alcohol intake or Western diet feeding also significantly promoted advanced neoplasia and PDAC development in Pdx1Cre;LSL-KrasG12D mice compared with mice fed a regular chow. Alcohol, but not Western diet, increased tumor development in the liver in the Pdx1Cre;LSL-KrasG12D mice, but its origin remained elusive due to leakiness of Pdx1Cre in hepatocytes. RNA-seq analysis revealed that alcohol feeding increases expression of markers for tumors (Epcam, Krt19, Prom1, Wt1, and Wwtr1), stroma (Dcn, Fn1, and Tnc), and cytokines (Tgfb1 and Tnf) and decreases expression of Fgf21 and Il6 in the pancreatic tumor tissues. Immunostaining showed heterogeneous expression of nephronectin, S100 calcium-binding protein A6, and vascular cell adhesion molecule 1 in pancreatic tumors surrounded by podoplanin-positive stromal cells. Our data indicate that moderate alcohol drinking is a risk factor for development of PDAC.NEW & NOTEWORTHY Heavy alcohol intake has been suspected to be a risk factor of pancreatic ductal adenocarcinoma (PDAC) in humans. However, the contribution of moderate alcohol intake to PDAC development remains elusive. In the present study, we experimentally show that moderate alcohol feeding significantly induces advanced stages of pancreatic intraepithelial neoplasia development and invasive PDAC in Pdx1Cre;LSL-KrasG12D mutant mice. Our data indicate that moderate alcohol drinking is a risk factor for PDAC. | Authentic |
Text : Cellular therapies are a rapidly evolving approach to treat cancer in the light of their unique mechanism of action that potentially overcomes drug resistance and induces durable remissions. Modalities of adoptive cell therapy include gene-modified T cells expressing novel T cell receptors or chimeric antigen receptors (CAR) that modify the immune system to recognize tumor cells and carry out potent anti-tumor effector functions. CAR T cells have shown very promising clinical results and several trials are being conducted worldwide to establish their role in cancer treatment. Most successful results have been observed in lymphoproliferative disorders with the use of CD19-directed CAR T cells, which led to their commercial approval by FDA. In this review, we provide a comprehensive overview of the current role of CAR T cell therapies in hematological malignancies and solid tumors, their associated toxicities and potential future developments in the armamentarium for cancer treatment. | Authentic |
Text : The evolutionarily conserved Hedgehog (Hh) signaling pathway have critical roles in development and homeostasis of tissues. Under physiological conditions, Hh is controlled at different levels via stem cell maintenance and tissue regeneration. Aberrant activation of this signaling pathway may occur in a wide range of human diseases including different types of cancer. In this review we present a concise overview on the key genes composing Hh signaling pathway and provide recent advances on the molecular mechanisms that regulate Hh signaling pathway from extracellular and receptors to the cytoplasmic and nuclear machinery with a highlight on the role of microRNAs. Furthermore, we focus on critical studies demonstrating dysregulation of the Hh pathway in human disease development, and potential therapeutic implications. Finally, we introduce recent therapeutic drugs acting as Shh signaling pathway inhibitors, including those in clinical trials and preclinical studies. | Authentic |
Text : In this study, a dichloromethane fraction (DCMF) from 70% Auricularia auricula-judae ethanol extract showed the highest level of antitumor activity compared to other solvent fractions (ethyl acetate, butanol, and water). The DCMF was found to have more potent antitumor activity against broncheoalveolar cancer (half maximal inhibitory concentration = 57.2 µg/mL) and gastric cancer cells (half maximal inhibitory concentration = 73.2 µg/mL) compared to the other solvent fractions, although all fractions inhibited the proliferation of the tumor cells in a dose-dependent manner. We further analyzed the DCMF composition by gas chromatography-coupled mass spectroscopy. Based on the results of this analysis, an antitumor active component (diazane) was identified in the DCMF. However, we found that diazane alone had a lower level of antitumor activity than the DCMF. These findings indicate that other unknown components of the DCMF also are responsible for the cytotoxic effects of DCMF against tumor cells. Semiquantitative reverse transcription polymerase chain reaction analysis demonstrated that DCMF induced cytotoxicity or tumor cell apoptosis as a result of the downregulation of Bcl-2 expression and p53 overexpression. Taken together, our study results demonstrated that the DCMF may be used as a functional additive for enhancing antioxidant activities and suppressing tumor growth in the body. | Authentic |
Text : The rapid development of science and technology has become an indispensable part of human life. Minimally invasive lung cancer surgery, that is, thoracoscopic surgery and da Vinci robotic surgery, has many advantages over previous surgeries, there is no need to make a large incision in the chest, the patient after such surgery, and recovery is also better and can also reduce the incision of the operation. Therefore, with the rapid development of science and technology today, how to detect changes in patients' health and establish an intelligent health monitoring system has become a development trend. This paper proposes to apply health monitoring in CYP1B1 gene polymorphism and nursing after clinical treatment of minimally invasive lung cancer surgery, after analyzing the society's demand for real-time health monitoring in this paper. It also studies the health monitoring system based on the advantages of smart phones. The system is suitable for the Android operating system and can monitor the temperature, weight, and other data of the human body. The experimental results show that the data value of the information displayed by the android software has a high degree of matching with the measured value, which basically keeps floating around 80, and the data consistency is strong. | Authentic |
Text : MicroRNAs are a class of small non-coding RNA molecules that play crucial roles in the initiation and progression of lung cancer. This study was undertaken to investigate the expression and roles of miR-186 in lung cancer. Ectopic expression experiments demonstrated that miR-186 functions as a tumor suppressor. Bioinformatic predictions, a luciferase reporter assay, and protein expression analysis suggested that miR-186 could inhibit the protein levels of SIRT6, a purported tumor suppressor gene. Collectively, our results indicated that miR-186 could inhibit lung cancer progression through targeting SIRT6 and that miR-186 may be a therapeutic target for lung cancer. | Authentic |
Text : Immune checkpoint inhibitors (ICIs) have transformed the therapeutic strategy and prognosis of advanced non-small cell lung cancer (NSCLC) patients. Nowadays, ICIs as monotherapy or in combination with chemotherapy are the standard of care treatment in advanced NSCLC, and in stage III, durvalumab (a programmed death ligand 1 inhibitor) is the unique drug approved as consolidation treatment after chemo-radiotherapy. This article reviews the pharmacological properties, clinical activity and safety of durvalumab as monotherapy or in combination with chemotherapy or other ICIs in the therapeutic strategy of NSCLC patients. | Authentic |
Text : Endometrial carcinoma (EC) is one of the most common gynecological cancers in many developing countries. Although tremendous advances have been made in the diagnosis and treatment of EC, there is still no adequate biomarker currently available for predicting the prognosis of this cancer. In this study, we found that miR-103 expression was significantly upregulated in EC tissues than their paired non-carcinoma tissues. Overexpression of miR-103 significantly promoted EC cell proliferation, while downregulation of miR-103 significantly suppressed EC cell proliferation. In addition, ZO-1 expression was significantly downregulated in the EC tissues than their paired non-carcinoma tissues. We also found an inverse correlation between ZO-1 and miR-103. Moreover, ZO-1 was validated as the direct target of miR-103. The downregulation of ZO-1 significantly enhanced EC cell proliferation. In conclusion, miR-103 could regulate EC cell proliferation through directly targeting ZO-1. Our results provide a potential development of microRNA-based targeted approaches for the treatment of EC. | Authentic |
Text : Transurethral resection of bladder tumors (TURBT) is the main surgical treatment for bladder cancer, but during TURBT, it is easy to stimulate the obturator nerve passing close to the lateral side of the bladder wall and induce involuntary contraction of the adductor muscle group of the thigh innervated by it, which will affect the surgical process and lead to adverse reactions. Obturator nerve block (ONB) helps to prevent the obturator nerve reflex. This study systematically evaluated and meta-analyzed the reports on the co-application of ONB and spinal anesthesia (SA) in TURBT in recent years to provide evidence for clinical diagnosis and treatment. The clinical randomized controlled literature studies of ONB combined with SA in TURBT published in PubMed, EMBASE, the Cochrane Library, CNKI (China National Knowledge Infrastructure), and Wanfang databases from January 2000 to December 2021 were searched. After screening the qualified literature studies, the literature quality was assessed by the Jadad scale. The incidence of obturator nerve reflex, the incidence of bladder perforation, length of hospital stay, and tumor recurrence rate were used as outcome indicators. The meta-analysis was performed with the R language toolkit. A total of 444 articles were initially retrieved, and after the screening, a total of 8 articles were included in the selection, and a total of 635 patients with ureterovesical tumor resection were included. The meta-analysis showed that the use of SA + ONB anesthesia during TURBT was associated with a smaller incidence of bladder perforation (RR = 0.24, 95% CI (0.11, 0.53), Z = -3.48, P=0.0005), a smaller incidence of obturator nerve reflex (RR = 0.22, 95% CI (0.13, 0.36), Z = -6.11, P=0.0001), a significantly shorter length of hospital stay (MD = -1.81, 95% CI (-2.65, -0.97), Z = -4.24, P=0.0001), and a significantly lower tumor recurrence rate (RR = 0.46, 95% CI (0.29, 0.73), Z = -3.30, P=0.001) compared with SA alone. The application of SA combined with ONB in TURBT can effectively reduce the incidence of obturator nerve reflex, reduce the incidence of bladder perforation, shorten the hospital stay and reduce the tumor recurrence rate. | Authentic |
Text : The highly refractory nature of non-small cell lung cancer (NSCLC) to chemotherapeutic drugs is an important factor resulting in its poor prognosis. Recent studies have revealed that tumour necrosis factor alpha-induced protein 8 (TNFAIP8) is involved in various biological and pathological processes of cells, but their underlying mechanisms in processes ranging from cancer development to drug resistance have not been fully elucidated. TNFAIP8 expression in clinical NSCLC samples was examined through immunohistochemistry (IHC). After adjusting for patients' characteristics with propensity score matching, Kaplan-Meier analysis and Cox regression analysis were performed for comparison of patients' survival according to the TNFAIP8 level. Lentiviral transfection with TNFAIP8-specific shRNAs was used to establish stable TNFAIP8 knockdown (TNFAIP8 KD) NCI-H460, A549 and cis-diamminedichloroplatinum II resistant A549 (A549/cDDP) cell lines. Cell proliferation and viability were assessed by CCK-8 assay. Cell cycle was examined by flow cytometry. Multiple pathways regulated by TNFAIP8 KD were revealed by microarray analysis. We found that high TNFAIP8 expression was associated with advanced pT stage, advanced pTNM stage, lymph node metastasis and unfavourable survival in NSCLC patients. TNFAIP8 shRNAs reduced in vitro cancer cell proliferation and in vivo tumor growth. Additionally, TNFAIP8 KD increased the sensitivity of NSCLC cells to cisplatin in vitro and in vivo. Conversely, up-regulation of TNFAIP8 promoted the proliferation and drug resistance to cisplatin of NSCLC cells. TNFAIP8 influences cancer progression pathways involving the MDM2/p53 pathway. Indeed, we observed that TNFAIP8 KD mediated the MDM2 downregulation and the p53 ubiquitination, thereby decreasing the degradation of p53 protein. shRNA p53 reversed TNFAIP8 shRNA-mediated regulation of cell proliferation, cell cycle, cisplatin sensitivity, and expression levels of RAD51, a DNA repair gene. Our work uncovers a hitherto unappreciated role of TNFAIP8 in NSCLC proliferation and cisplatin chemoresistance that is mediated through the MDM2/p53 pathway. These findings might offer potential therapeutic targets for reversing cisplatin resistance in NSCLC patients with high TNFAIP8 expression. | Authentic |
Text : The aim of this study was to explore the molecular function of long intergenic noncoding RNA 00511 (LINC00511) and its target proteins in recurrent breast cancer after breast-conserving surgery followed by radiotherapy. LINC00511 expression in tissues was measured by quantitative polymerase chain reaction (qPCR). The association between LINC00511 expression and the clinicopathological features of breast cancer was analyzed by Chi-square tests. The impact of LINC00511 on overall survival was evaluated by the log-rank test. MDA-MB-231/MDA-MB-436 cell lines transfected with short hairpin RNA (shRNA) were used to investigate the influence of LINC00511 silencing on tumor growth and radiosensitivity in vitro and in vivo. A series of experiments including cell apoptosis assay, cell colony formation assay, and mouse xenograft models were applied to test those transfected cell lines. MicroRNA (miRNA) targets of LINC00511 were identified by bioinformatics analysis and further validated by dual luciferase reporter assay, qPCR, and Western blot analysis. LINC00511 expression was significantly increased in breast cancer tissues and correlated with recurrence and poor survival after breast-conserving surgery followed by radiotherapy. LINC00511 knockdown by shRNA restricted cell proliferation, promoted cell apoptosis, and enhanced radiosensitivity in vitro, and inhibited tumor growth with an increased response to radiation in vivo. In addition, elevated LINC00511 was found to increase syntaxin-binding protein 4 (STXBP4) expression through competitive binding to miR-185, while silencing LINC00511 decreased STXBP4 expression and increased radiosensitivity. LINC00511 inhibition impairs its competitive binding to miR-185, resulting in increased STXBP4 expression and improved radiation response in breast cancer. Our study results suggest that the LINC00511/miR-185/STXBP4 axis may be a promising therapeutic target for improving the prognosis of breast cancer. | Authentic |
Text : To investigate the association between level of serum ferritin (SF) and epidermal growth factor receptor (EGFR) mutations and to analyse the impact of SF level on survival times in advanced non-small-cell lung cancer (NSCLC) patients taking EGFR tyrosine kinase inhibitors (EGFR-TKIs). A total of 301 patients who were admitted to the Chinese PLA general hospital from August 2015 to August 2017 were enrolled. The association between tumour markers, including SF, CEA, and EGFR mutation, and their impact on the prognosis of patients taking EGFR-TKIs was investigated. In all patients, the percentage of patients with EGFR mutations was 52.5% (158/301). EGFR mutations were more likely to be detected in younger (<60 years old), adenocarcinoma patients, non-smokers, women, CEA≥5 µg/L and serum ferritin ≥129 µg/L for females or ≥329 µg/L for males (p<0.05). Increased serum ferritin was an independent factor for predicting EGFR mutations (odds ratio (OR)=4.593, 95% CI (2.673-7.890); P <0.001), and an area under curve (AUC) of 0.711 was shown to predict EGFR mutations with a sensitivity of 81.7% and a specificity of 65.2% in women. Sensitivity increased to 91.1% when combining SF and CEA in all patients. SF was also an independent factor (HR=3.531, 95% CI (2.288-5.448); P<0.001) for predicting progression-free survival (PFS) of patients on EGFR-TKIs, analysed by a Cox proportional hazard model, as PFS was shorter in patients with higher SF (15.0 mo. (SF < 129 µg/L for females or <329 for males) vs 10.0 mo. (129-258 µg/L for females or 329-658 µg/L for males) vs 7.3 mo. (>258 µg/L (>258 µg/L for females or >658 µg/L for males) p<0.001). SF was a significant predictor of EGFR mutation with moderate diagnostic accuracy, and combining SF and CEA increased the diagnostic sensitivity and specificity for EGFR mutations. SF was also useful for predicting survival in EGFR-TKIs. | Authentic |
Text : Recovery rates for B-cell Non-Hodgkin's Lymphoma (NHL) are up to 70% with current standard-of-care treatments including rituximab (chimeric anti-CD20 monoclonal antibody) in combination with chemotherapy (R-CHOP). However, patients who do not respond to first-line treatment or develop resistance have a very poor prognosis. This signifies the need for the development of an optimal treatment approach for relapsed/refractory B-NHL. Novel CD19- chimeric antigen receptor (CAR) T-cell redirected immunotherapy is an attractive option for this subset of patients. Anti-CD19 CAR T-cell therapy has already had remarkable efficacy in various leukemias as well as encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. In going forward with additional clinical trials, complementary treatments that may circumvent potential resistance mechanisms should be used alongside anti-CD19 T-cells in order to prevent relapse with resistant strains of disease. Some such supplementary tactics include conditioning with lymphodepletion agents, sensitizing with kinase inhibitors and Bcl-2 inhibitors, enhancing function with multispecific CAR T-cells and CD40 ligand-expressing CAR T-cells, and safeguarding with lymphoma stem cell-targeted treatments. A therapy regimen involving anti-CD19 CAR T-cells and one or more auxiliary treatments could dramatically improve prognoses for patients with relapsed/refractory B-cell NHL. This approach has the potential to revolutionize B-NHL salvage therapy in much the same way rituximab did for first-line treatments. | Authentic |
Text : Emerging evidence continues to highlight the significant role of microRNAs (miRNAs) in the regulation of cancer growth and metastasis. Herein, the current study aimed to elucidate the role of exosomal miR-183 in prostate cancer development. Initially, public microarray-based gene expression profiling of prostate cancer was employed to identify differentially expressed miRNAs. The putative target gene TPM1 of miR-183 was subsequently predicted, followed by the application of a luciferase reporter assay and examination of the expression patterns in prostate cancer patients and cell lines. The effects of miR-183 and TPM1 on processes such as cell proliferation, invasion and migration were evaluated using in vitro gain- and loss-of-function experiments. The effect of PC3 cells-derived exosomal miR-183 was validated in LNCaP cells. In vivo experiments were also performed to examine the effect of miR-183 on prostate tumor growth. High expression of miR-183 accompanied with low expression of TPM1 was detected in prostate cancer. Our data indicated that miR-183 could target and downregulate TPM1, with the overexpression of miR-183 and exosomal miR-183 found to promote cell proliferation, migration, and invasion in prostate cancer. Furthermore, the tumor-promoting effect of exosome-mediated delivery of miR-183 was subsequently confirmed in a tumor xenograft model. Taken together, the key findings of our study demonstrate that prostate cancer cell-derived exosomal miR-183 enhance prostate cancer cell proliferation, invasion and migration via the downregulation of TPM1, highlighting a promising therapeutic target against prostate cancer. | Counterfeit |
Text : The aim of this meta-analysis was to assess the association between beta-microseminoprotein gene (MSMB) rs10993994 polymorphism and prostate cancer (PCa) risk. Relevant databases were searched to identify studies investigating the association between rs10993994 polymorphisms and the risk of PCa using allele contrast, recessive, dominant, and additive models. The assessment of the association was used by odds ratios (ORs) with 95% confidence intervals (CIs). Hardy-Weinberg equilibrium (HWE) was checked for each study. The sensitivity analysis and the assessment of publication bias were also performed. Six reports involving 13 eligible studies (a total of 11,385 PCa patients and 9,115 controls) were included in the meta-analysis. Our data revealed that the T allele of MSMB rs10993994 polymorphism was significantly associated with PCa in all subjects (allele contrast: OR=1.24, 95% CI=1.19-1.29, p<0.001). Similarly, for recessive, dominant, and additive genetic models, significant associations were also found (recessive: OR=1.40, 95% CI=1.30-1.51; dominant: OR=1.28, 95% CI=1.21-1.36; and additive: OR=1.56, 95% CI=1.44-1.70). Significant associations were also found in Caucasians. The data for Asians showed significant association in allele contrast and recessive, additive genetic models, whereas no statistical significance was found in the dominant genetic model. This study demonstrated a significant association between the MSMB rs10993994 polymorphisms and PCa risk. Further large-scale studies are warranted to confirm our findings. | Authentic |
Text : The immune checkpoint blockade is an effective strategy to enhance the anti‑tumor T cell effector activity, thus becoming one of the most promising immunotherapeutic strategies in the history of cancer treatment. Several immune checkpoint inhibitor have been approved by the FDA, such as anti‑CTLA‑4, anti‑PD‑1, anti‑PD‑L1 monoclonal antibodies. Most tumor patients benefitted from these antibodies, but some of the patients did not respond to them. To increase the effectiveness of immunotherapy, including immune checkpoint blockade therapies, miniaturization of antibodies has been introduced. A single‑domain antibody, also known as nanobody, is an attractive reagent for immunotherapy and immunoimaging thanks to its unique structural characteristic consisting of a variable region of a single heavy chain antibody. This structure confers to the nanobody a light molecular weight, making it smaller than conventional antibodies, although remaining able to bind to a specific antigen. Therefore, this review summarizes the production of nanobodies targeting immune checkpoint molecules and the application of nanobodies targeting immune checkpoint molecules in immunotherapy and immunoimaging. | Authentic |
Text : Growing evidence indicates that aberrant expression of microRNAs contributes to tumor development. However, the biological role of microRNA-4490 (miR-4490) in gastric cancer (GC) remains to be clarified. To explore the function of miR-4490 in GC, we performed colony formation, EdU incorporation, qRT-PCR, Western blotting, in situ hybridization (ISH), immunohistochemistry (IHC), flow cytometry, ChIP and dual-luciferase reporter assays. In addition, the growth, migration and invasion capacities of GC cells were evaluated. We found that miR-4490 was significantly downregulated in primary GC samples and in GC-derived cell lines compared with normal controls, and that this expression level was negatively correlated with GC malignancy. Exogenous miR-4490 expression not only reduced cell cycle progression and proliferation, but also significantly inhibited GC cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, we found that miR-4490 directly targets USP22, which mediates inhibition of GC cell proliferation and EMT-induced metastasis in vitro and in vivo. Moreover, we found through luciferase and ChIP assays that transcription factor POU2F1 can directly bind to POU2F1 binding sites within the miR-4490 and USP22 promoters and, by doing so, modulate their transcription. Spearman's correlation analysis revealed a positive correlation between USP22 and POU2F1 expression and negative correlations between miR-4490 and USP22 as well as miR-4490 and POU2F1 expression in primary GC tissues. Based on our results we conclude that miR-4490 acts as a tumor suppressor, and that the POU2F1/miR-4490/USP22 axis plays an important role in the regulation of growth, invasion and EMT of GC cells. | Authentic |
Text : Rearrangement and amplification of the D-type cyclin genes have been reported in human cancer. Previous studies have demonstrated that Ras-mediated skin tumorigenesis depends on pathways that act through cyclin D1 and D2; however, the role of cyclin D3 remains unknown. The present study demonstrates that cyclin D3 ablation does not affect keratinocyte proliferation, but instead increases apoptosis levels in the bulge region of the hair follicle. Consequently, cyclin D3 ablation reduces skin papilloma development in a Ras-dependent carcinogenesis model. Previous results revealed that cyclin D3 preferentially binds to cyclin-dependent kinase 6 (CDK6) in mouse keratinocytes and transgenic expression of CDK6 (K5CDK6 mice) inhibits skin tumor development. Thus, we hypothesized that the inhibitory effect of CDK6 is dependent on cyclin D3 expression. To test this hypothesis, a mouse model that overexpresses CDK6 and does not express cyclin D3 (K5CDK6/cyclin D3-/- compound mouse) was developed. Biochemical analysis of the epidermis of K5CDK6/cyclin D3-/- mice revealed that cyclin D3 ablation resulted in increased expression of cyclin D1 protein, with a consequent elevation in the level of CDK6/cyclin D1 and CDK4/cyclin D1 complexes. These findings were concurrent with the increase skin papilloma malignant progression observed in K5CDK6/cyclin D3-/- mice. In summary the absence of cyclin D3 led to fewer number of papillomas in cyclin D3-ablated mice than in the wild-type owing to increased apoptosis, suggesting that alterations in cell survival are a crucial mechanism for crippling cellular defense against neoplasia. The results of the current study also suggest that although cyclin D3 expression does not alter the tumor suppressive role of CDK6 in skin carcinogenesis, the compensatory increase in cyclin D1 can shift the balance towards malignant progression. | Authentic |
Text : Klotho is a recently discovered anti‑aging gene, which has been reported as a tumor suppressor in numerous human malignancies; however, the role of Klotho in human ovarian cancer remains to be elucidated. The aim of the present study was to detect the expression of Klotho and evaluate its association with the progression of human ovarian cancer. A clinical follow‑up study of 120 patients with ovarian cancer and 78 normal controls was conducted. The expression levels of Klotho were determined by western blotting and immunohistochemistry. The results demonstrated that high Klotho expression levels were detected in all normal controls, whereas the positive rate of Klotho was 61.6% in the ovarian cancer group, which was significantly decreased compared with in the control group (P<0.01). Furthermore, reduced Klotho expression was significantly correlated with decreased survival rates in patients with ovarian cancer (P=0.025). Subsequently, Klotho levels were detected in seven human ovarian cancer cell lines by western blotting. The results demonstrated that the highest levels of Klotho were detected in CaOV3 cells, medium levels of Klotho were detected in CaOV4 and SKOV‑3 cells, and almost no Klotho was detected in the other four cell lines: OVCA 432, OVCAR‑5, OVCAR‑8 and A2780 cells. The association between Klotho levels and cell proliferation was determined by MTT assay, and the results indicated that higher levels of Klotho inhibited the proliferation of A2780 and OVCAR‑5 cells, whereas reduced Klotho expression promoted cell growth of CaOV3 and SKOV‑3 cells. In addition, the plasma levels of inflammatory cytokines in tumor‑bearing mice and normal control mice were detected by enzyme‑linked immunosorbent assay, and plasma interleukin (IL)‑6 and IL‑1β levels were elevated in all tumor‑bearing mice. Notably, the mRNA expression levels of IL‑6 were significantly higher in the liver, ovaries and kidneys of Klotho‑/‑ mice compared with in wild type mice (P<0.01), thus indicating that aberrant Klotho expression may contribute to systemic inflammation in Klotho‑/‑ mice. Finally, the in vivo antitumor role of aberrant Klotho expression was determined in a nude mice model. A2780 cells were transfected with pCMV6‑Klotho and the stably transfected cells were screened; the mice were injected with the stably transfected cells. The results indicated that tumor volume and tumor weight were significantly decreased in the pCMV6‑Klotho group compared with in the pCMV6 vector group (P<0.01). These findings suggest that overexpression of Klotho may suppress tumor growth in animal models. In conclusion, Klotho was demonstrated to act as a potent tumor suppressor in human ovarian cancer cells. Reduced Klotho expression was detected in the specimens of patients with ovarian cancer, and overexpression of Klotho significantly inhibited cell proliferation of human ovarian cancer cells. Therefore, Klotho may be considered a useful key target for the molecular therapy of human ovarian cancer. | Authentic |
Text : Combination chemotherapy is a rational strategy to increase patient response and tolerability and to decrease adverse effects and drug resistance. Recently, the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been reported to be associated with reduction in occurrence of a variety of cancers including lung cancer. On the other hand, growing evidences suggest that deuterium-enriched water (DEW, D2O) and deuterium-depleted water (DDW) play a role both in treatment and prevention of cancers. In the present study, we examined the effects of DEW and DDW in combination with two NSAIDs, celecoxib and indomethacin, on A549 human non-small lung cancer cell to identify novel treatment options. The cytotoxicity of celecoxib or indomethacin, alone and in combination with DDW and DEW was determined. The COX-2, MAPK pathway proteins, the anti-apoptotic Bcl2 and pro-apoptotic Bax proteins and caspase-3 activity were studied for cytotoxic combinations. Co-administration of selective and non-selective COX-2 inhibitors with DEW led to a remarkable increase in cytotoxicity and apoptosis of A549 cells. These events were associated with activation of p38 and JNK MAPKs and decreasing pro-survival proteins Bcl-2, COX-2 and ERK1/2. Furthermore, the combination therapy activated caspase-3, and the apoptosis mediator, and disabled poly ADP-ribose polymerase (PARP), the key DNA repair enzyme, by cleaving it. The combination of DEW with NSAIDs might be effective against lung cancer cells by influence on principal cell signalling pathways, and this has a potential to become a candidate for chemotherapy. | Authentic |
Text : Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has significant potential for application in the treatment of urothelial carcinoma (URCa) of the bladder. Previous studies have shown that regulation of the AMP-activated serine/threonine protein kinase (AMPK)-mTOR signaling pathway enhances apoptosis by inducing autophagy or mitophagy in bladder cancer. Alteration of liver kinase B1 (LKB1)-AMPK signaling leads to mitochondrial dysfunction and the accumulation of autophagy-related proteins as a result of mitophagy, resulting in enhanced cell sensitivity to drug treatments. Therefore, we hypothesized that LKB1 deficiency in URCa cells could lead to increased sensitivity to rapamycin by inducing mitochondrial defect-mediated mitophagy. To test this, we established stable LKBI-knockdown URCa cells and analyzed the effects of rapamycin on their growth. Rapamycin enhanced growth inhibition and apoptosis in stable LKB1-knockdown URCa cells and in a xenograft mouse model. In spite of the stable downregulation of LKB1 expression, rapamycin induced AMPK activation in URCa cells, causing loss of the mitochondrial membrane potential, ATP depletion, and ROS accumulation, indicating an alteration of mitochondrial biogenesis. Our findings suggest that the absence of LKB1 can be targeted to induce dysregulated mitochondrial biogenesis by rapamycin treatment in the design of novel therapeutic strategies for bladder cancer. | Authentic |
Text : Cancer remains one of the leading causes of death worldwide in humans and animals. Conventional treatment regimens often fail to produce the desired outcome due to disturbances in cell physiology that arise during the process of transformation. Additionally, development of treatment regimens with no or minimum side-effects is one of the thrust areas of modern cancer research. Oncolytic viral gene therapy employs certain viral genes which on ectopic expression find and selectively destroy malignant cells, thereby achieving tumor cell death without harming the normal cells in the neighborhood. Apoptin, encoded by Chicken Infectious Anemia Virus' VP3 gene, is a proline-rich protein capable of inducing apoptosis in cancer cells in a selective manner. In normal cells, the filamentous Apoptin becomes aggregated toward the cell margins, but is eventually degraded by proteasomes without harming the cells. In malignant cells, after activation by phosphorylation by a cancer cell-specific kinase whose identity is disputed, Apoptin accumulates in the nucleus, undergoes aggregation to form multimers, and prevents the dividing cancer cells from repairing their DNA lesions, thereby forcing them to undergo apoptosis. In this review, we discuss the present knowledge about the structure of Apoptin protein, elaborate on its mechanism of action, and summarize various strategies that have been used to deliver it as an anticancer drug in various cancer models. | Authentic |
Text : Activation of the inflammatory signaling pathway is the most vital part of the pre-metastatic events of breast cancer. Platycodin D (PlaD) shows favorable pharmacological activities in anti-inflammatory and anti-tumor effect. The main purpose of this study was to survey the effects of PlaD on S100A8/A9-induced inflammation in mouse mammary carcinoma 4T1 cells. S100A8/A9 immunolocalization and expression in pre-metastatic lung tissue were assessed by immunofluorescence staining and ELISA. 4T1 cells were treated with 2.5 μg/mL recombinant S100A8/A9 heterodimer and 7.5, 10, or 12.5 μM of PlaD. After 24 h of incubation, cell viability, migration, and invasion were evaluated by CCK-8, wound-healing, and transwell assay, respectively. Nuclear translocation of NF-κB p65 was determined by immunostaining and western blot. The levels of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α were detected by ELISA. The results showed that S100A8/A9 was actively increased and released into the extracellular space during the pre-metastatic phase of breast cancer. PlaD treatment attenuated S100A8/A9-induced growth, migration, and invasion of 4T1 cells. Furthermore, PlaD decreased the levels of IL-1β, IL-6, and TNF-α by inhibiting nuclear translocation of NF-κB p65. In conclusion, this study demonstrated that PlaD inhibited S100A8/A9-induced inflammatory response in 4T1 cells by suppressing the expression of IL-6, IL-1β, and TNF-α via inhibition of NF-κB signaling pathways. | Authentic |
Text : In this study, we examined the expression of GINS2 in glioma and determined its role in glioma development. The protein expression of GINS2 was assessed in 120 human glioma samples via immunohistochemistry. Then, we suppressed the expression of GINS2 in glioma cell strains U87 and U251 using a short hairpin RNA lentiviral vector. In addition, RNA sequencing and bioinformatics analysis were performed on glioma cells before and after GINS2 knockdown. Subsequent co-immunoprecipitation and western blot experiments indicated possible downstream regulatory molecules. The present results showed that GINS2 can accelerate the growth of glioma cells, whereas the suppression of GINS2 expression decreased the proliferation and tumorigenicity of glioma cells. Mechanism research experiments proved that GINS2 can block the cell cycle by regulating certain downstream molecules, such as MCM2, ATM, and CHEK2. GINS2 is closely related to the occurrence and development of glioma, and is likely to become a prognostic marker for glioma patients, as well as a potential therapeutic target in the treatment of glioma. | Authentic |
Text : The aim of the study is to analyze the serological features, etiology, and prognosis of congenital hypothyroidism (CH) treated with L-thyroxine sodium (L-T4). A total of 126 CH children in our hospital from June 2015 to January 2020 were selected as the research objects, and L-T4 treatment was given immediately after diagnosis. After diagnosis and 24 months of treatment, laboratory serum thyroid function-related indicators were examined, and thyroid changes were determined by ultrasound. We compared serum thyroxine levels in children with different thyroid changes, compared serum thyroid hormone levels, serum ghrelin levels, and body mass index (BMI) changes in children with CH before treatment and after 24 months of treatment, and analyzed the prognosis of treatment in children. In terms of thyroid changes in 126 CH children, 32 cases (25.40%) had a normal thyroid gland, 16 cases (12.70%) had a hypoplastic thyroid gland, 40 cases (31.75%) had an ectopic thyroid gland, 28 cases (22.22%) had an absent thyroid gland, and 10 cases (7.93%) had an enlarged thyroid gland, with an ectopic thyroid gland being the most common. In terms of serological expression of CH children, the TSH level in children with thyroid dysplasia was significantly higher than that in children with basic normal and T3 and T4 levels were significantly lower than those in children with basic normal (P < 0.05). At the same time, the TSH level in children with thyroid absence, ectopic, and enlargement was increased, while thyroxine (T4) and tri-iodothyronine (T3) levels were decreased compared with those in children with thyroid dysplasia. The difference was statistically significant (P < 0.05). Univariate analysis showed that there were statistically significant differences in birth weight, week of gestation at delivery, maternal age at childbirth, household registration, and a family history of thyroid disease compared between the two groups (P < 0.05); multivariate logistic regression analysis showed that birth weight <2,500 g, maternal age >35 years, rural residence, and a family history of thyroid disease were risk factors for neonatal CH (P < 0.05). Serum thyroid-stimulating hormone (TSH) levels, serum ghrelin levels, and the body mass index of children with CH decreased significantly, and T4 levels increased significantly after 24 months of treatment (P < 0.05). Screening for common causes of CH is conducive to timely detection of children with CH, and L-T4 treatment can effectively improve thyroid function in children. | Counterfeit |
Text : Although galectin-1 and integrin α5β1 confer chemoresistance to certain types of cancer, whether their expression predicts the response to cisplatin-based neoadjuvant chemotherapy (NACT) in squamous cervical cancer remains unclear. Paired tumor samples (pre- and post-chemotherapy) were obtained from 35 bulky squamous cervical cancer patients treated with cisplatin-based NACT and radical hysterectomy at our hospital between January 2007 and August 2014. The expression of galectin-1 and integrin α5β1 in tumor cells and stromal cells was analyzed by immunohistochemistry. The correlation between galectin-1/integrin α5β1 and apoptosis-associated markers was investigated by using the The Cancer Genome Atlas (TCGA) RNA-sequencing data. Seventeen patients were identified as chemotherapy responders and 18 as non-responders. Galectin-1 and integrin α5β1-positive immunostaining was more frequently observed in stromal cells than its in tumor cells. The expression of galectin-1 and integrin α5β1 in stromal and tumor cells was significantly down-regulated in postchemotherapy cervical cancer tissues. High levels of galectin-1 and integrin α5β1 in stromal were associated with a negative chemotherapy response in squamous cervical cancer patients treated with cisplatin-based NACT. Additionally, the expression of galectin-1 and integrin α5 correlated negatively with caspase 3/caspase 8 by using the TCGA RNA-sequencing data. Galectin-1 and integrin α5β1 expression in stromal may serve as a prediction of the responses to cisplatin-based NACT for patients with bulky squamous cervical cancer. Galectin-1 and integrin α5β1 may be implicated in the development of chemoresistance in cervical cancer via suppressing apoptosis. | Authentic |
Text : BHLHE41 has been shown to be a marker of tumorigenesis. Colon cancer (CC) is a common malignant tumor of colonic mucosa. This study mainly explored the mechanism of BHLHE41 in alleviating malignant behavior of hypoxia-induced CC cells. The levels of BHLHE41 in CC and normal cell lines were tested by Western blot and qRT-PCR. After, CC cells were subjected to hypoxia treatment and BHLHE41 overexpression transfection, and the BHLHE41 expression, the effect of BHLHE41 on CC cell viability, apoptosis, migration, and invasion and cell cycle were tested by qRT-PCR and relevant cell functional experiments. HIF-1α and epithelial-mesenchymal transition- (EMT-) related proteins were tested by Western blot. Moreover, CC tumor-bearing model was established in nude mice, and the effect of BHLHE41 on the tumor was evaluated by measuring the tumor volume and weight. Then, the expressions of BHLHE41 and EMT-related proteins were detected by immunohistochemistry and Western blot. Western blot and qRT-PCR showed that BHLHE41 was lowly expressed in CC cells. BHLHE41 overexpression could inhibit the hypoxia-induced CC cell viability, migration, and invasion, induce apoptosis, and alter cell cycle. Besides, BHLHE41 overexpression could enhance the levels of E-cadherin but reduce the levels of HIF-1α, N-cadherin, vimentin, and MMP9 in hypoxia-induced CC cells. Moreover, BHLHE41 overexpression reduced tumor volume, weight, and EMT-related proteins levels in tumor tissues. BHLHE41 overexpression could mitigate the malignant behavior of hypoxia-induced CC via modulating the HIF-1α/EMT pathway. | Authentic |
Text : Exosomal lncRNAs secreted by cancer cells can serve as potential biomarkers in the diagnosis and prognosis of various tumours. Here, we are committed to explore the diagnostic and prognostic value of serum exosomal XIST secreted by tumour cells to predict recurrence in patients with triple-negative breast cancer (TNBC). Significant increments in XIST and exo-XIST from tumour tissues and blood serum were found in reoccurring TNBC patients by comparison with non-recurrences. Levels of serum exo-XIST were only significantly increased in TNBC recurrence and no association with other clinicopathological parameters. Additionally, serum exo-XIST levels could be served as an assessment of change in the load of triple-negative breast cancer. Expressions of exo-XIST were markedly decreased after resection of the primary breast tumours and obviously elevated at the time of recurrence. Finally, an obvious association was identified between serum exo-XIST levels and a poorer overall survival (OS) in TNBC patients. Levels of serum exo-XIST may serve as a diagnostic and prognostic biomarker to predict the recurrent TNBC-loading status. | Authentic |
Text : Osteoblasts are implicated in the building of the vertebrate skeleton. The current study aimed to investigate the role of microRNA-495 (miR-495) in the osteoblasts of mice with tibial fractures and the underlying mechanism involving in aquaporin-1 (AQP1) and the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. Initially, a microarray-based analysis was performed to screen the differentially expressed genes and miRNAs associated with tibial fracture. Following the establishment of a tibial fracture mouse model, the positive rate of the AQP1 protein in the fracture tissue was detected by immunohistochemistry (IHC). Next, to verify the binding site between miR-495 on AQP1, bioinformatics data were employed in addition to the application of a dual-luciferase reporter gene assay. The osteoblast cell line MC3T3-E1 was treated with miR-495 mimic, miR-495 inhibitor and Anisomycin to explore the potent effects of miR-495 on proliferation and differentiation of osteoblasts in mice with tibial fracture. The expression of miR-495, AQP1, p38 MAPK, PCNA, Cyclin D1, OCN, and OPN was subsequently evaluated by RT-qPCR and Western blot analysis. Cell viability, the number of calcium nodules and alkaline phosphatase (ALP) activity were detected by MTT assay, alizarin red staining, and ALP activity assay, respectively. Our results revealed that miR-495 was down-regulated while AQP1 was up-regulated in the mice with tibial fractures. AQP1 was verified as a target gene of miR-495. When the cells were treated with overexpressed miR-495 or activated p38 MAPK signaling pathway, elevated expression of PCNA, Cyclin, D1, OCN, and OPN along with an increased amount of calcium nodules, higher cell viability, and enhanced ALP activity was detected, while the expression of AQP1 was reduced. Collectively, the key findings of the present study support the notion that overexpressed miR-495 may activate the p38 MAPK signaling pathway to inhibit AQP1 and to promote the proliferation and differentiation of osteoblasts in mice with tibial fracture. | Counterfeit |
Text : Metal-ion-based self-assembly supramolecular theranostics exhibit excellent performance in biomedical applications owing to their potential superiorities for simultaneous precise diagnosis, targeted drug delivery, and monitoring the response to therapy in real-time. Specially, the rational designed systems could achieve specific in vivo self-assembly through complexation or ionic interaction to improve tissue-specific accumulation, penetration, and cell internalization, thereby reducing toxicities of drugs in diagnostics and therapy. Furthermore, such imaging traceable nanosystems could provide real-timely information of drug accumulation and therapeutic effects in a non-invasive and safe manner. Herein, the article highlights the recent prominent applications based on the metal ions self-assembly in cancer treatment. This strategy may open up new research directions to develop novel drug delivery systems for cancer theranostics. | Authentic |
Text : Current international prognostic index is widely questioned on the risk stratification of peripheral T-cell lymphoma and does not accurately predict the outcome for patients. We postulated that multiple mRNAs could combine into a model to improve risk stratification and helping clinicians make treatment decisions. In this study, the gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was used to screening genes in selected module which most closely related to PTCLs, and then built a mRNA signature using a LASSO Cox regression model and validated the prognostic accuracy of it. Finally, a nomogram was constructed and the performance was assessed. A total of 799 WGCNA-selected mRNAs in black module were identified, and a mRNA signature which based on DOCK2, GSTM1, H2AFY, KCNAB2, LAPTM5 and SYK for PTCLs was developed. Significantly statistical difference can be seen in overall survival of PTCLs between low-risk group and high-risk group (training set:hazard ratio [HR] 4.3, 95% CI 2.4-7.4, P < .0001; internal testing set:hazard ratio [HR] 2.4, 95% CI 1.2-4.8, P < .01; external testing set:hazard ratio [HR] 2.3, 95% CI 1.10-4.7, P = .02). Furthermore, multivariate regression demonstrated that the signature was an independently prognostic factor. Moreover, the nomogram which combined the mRNA signature and multiple clinical factors suggesting that predicted survival probability agreed well with the actual survival probability. The signature is a reliable prognostic tool for patients with PTCLs, and it has the potential for clinicians to implement personalized therapeutic regimen for patients with PTCLs. | Authentic |
Text : To evaluate the patterns of vitamin and herbal supplement use among patients with advanced gastrointestinal (GI) cancers and the association of such behavior with the efficacy and toxicity of systemic anticancer treatment. Project data sphere (PDS) was used to access de-identified datasets of eight clinical trials of advanced GI cancers. Multivariable logistic regression analysis was used to identify factors predicting the use of supplements. Kaplan-Meier survival estimates were used to evaluate the association of supplement use with overall and progression-free survival. Results were stratified according to the site of the primary tumor [pancreatic, gastric, colorectal or hepatocellular carcinoma (HCC)] The association between supplement use and selected chemotherapy side effects was evaluated through Chi-squared testing and subsequent logistic regression. A total of 3441 patients were included in the analysis. Of these, 775 patients reported use of supplements and 2666 patients reported no use of supplements. Higher ECOG performance score (Odds ratio: OR for ECOG 1 versus 0: 1.629; 95% CI 1.363-1.947; P < 0.001) and pancreatic primary site (OR for gastric cancer versus pancreatic cancer: 0.538; 95% CI 0.408-0.709; P < 0.001) was associated with greater use of these supplements. Supplement use was associated with a better overall survival among patients with pancreatic cancer (P = 0.002) but not other GI malignancies. Supplement use was associated with a higher probability of anemia and diarrhea among patients with pancreatic cancer (P < 0.001 for both), gastric cancer (P = 0.016; P = 0.036, respectively) and colorectal cancer (P < 0.001 for both). There is an association between the use of vitamin and herbal supplements and a higher probability of hematologic and gastrointestinal toxicities. There is a need for more studies to confirm the association between such behavior and better overall survival among patients with pancreatic cancer. | Authentic |
Text : Differences in body mass index (BMI) were used to analyze the survival and prognosis of SCCHN patients. A retrospective cohort study was conducted to select 323 patients who underwent surgical treatment for SCCHN from June 2013 to June 2016. The patients were divided into a healthy BMI group (BMI<24kg/m2), an overweight group (24kg/m2≤BMI<28kg/m2) and an obese group (BMI≥28 kg/m2). Various statistical methods were used to summarize and analyze clinical data, complications, disease specific survival (DSS), the overall survival (OS), and recurrence-free survival (RFS) within the last 3 y. At 3 y, OS (54.40%) and DSS (51.94%) were slightly lower in the obese group compared with the overweight (64.62%, 61.92%) and healthy BMI groups (64.66%, 65.02%), but no statistical significance was found in DSS (P=0.178), OS (P=0.123) and RFS (P=0.362). The difference in operation duration (P=0.008) and bleeding volume (P=0.001) in obese patients was consistent with those in diabetes mellitus (P=0.002) and coronary heart disease (P=0.000). A high incidence of pharyngeal fistula was observed in obese (P=0.014) and overweight patients (P=0.025), but mouth floor fistula (P=0.038), lung infection (P=0.047), fat liquefaction (P=0.003) and lower extremities deep venous thrombosis (P=0.020) were only found in the obese group. Cox univariatable and multivariatable analysis showed that clinical stage, T stage, and N stage were independent prognostic factors for patients with SCCHN, which was not related to BMI. BMI was associated with a higher probability of complications. However, BMI had no significant correlation with 3-year OS, RFS and DSS, and was not a prognostic indicator for patients with SCCHN. | Authentic |
Text : Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Long noncoding RNAs (lncRNAs) play important roles in many diseases. Therefore, the aim of this study was to investigate the role of lncRNA ZFAS1 in the development of HCC and to explore its underlying mechanism. Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was utilized to detect ZFAS1 expression in tissue samples of HCC patients. Subsequently, Cell Counting Kit-8 (CCK-8) assay, colony formation assay, and EdU incorporation assay were performed to detect the function of ZFAS1 in vitro. Furthermore, mechanism assays were performed to explore the interaction between ZFAS1 and miR-193a-3p. ZFAS1 was significantly highly expressed in HCC tissues than that of adjacent normal tissues. The growth ability of HCC cells was markedly inhibited after ZFAS1 was silenced. However, the growth ability of HCC cells was remarkably promoted after ZFAS1 overexpression. Moreover, RT-qPCR results revealed that miR-193a-3p was significantly down-regulated via the overexpression of ZFAS1. However, miR-193a-3p was significantly up-regulated via the knockdown of ZFAS1. Further experiments showed that miR-193a-3p was a direct target of ZFAS1 in HCC. ZFAS1 could enhance the proliferation of HCC cells by suppressing miR-193a-3p, which might be a potential therapeutic target in HCC. | Authentic |
Text : This report presents our experience with T therapy in a cohort of T-deficient men on active surveillance (AS) for Gleason 3 + 3 and Gleason 3 + 4 prostate cancer (PCa). A retrospective chart review identified 28 men with T deficiency who underwent T therapy (T group) for at least 6 months while on AS for PCa. A comparison group of 96 men on AS for PCa with untreated T deficiency (no-T group) was identified at the same institution. The AS protocol followed a modified Epstein criteria and allowed inclusion of men with a single core of low-volume Gleason 3 + 4 PCa. Mean age was 59.5 and 61.3 years, and mean follow-up was 38.9 and 42.4 months for the T and no-T groups, respectively. Of all 28 men in the T group, 3 (10.7%) men developed an increase in Gleason score while on AS. Of 22 men in the T group with Gleason 3 + 3 disease, 7 (31.8%) men developed biopsy progression including 3 men (13.6%) who developed Gleason 3 + 4 PCa. Of 6 men with Gleason 3 + 4 disease at baseline, 2 (33.3%) men developed an increase in tumor volume, and none developed upgrading beyond Gleason 3 + 4. All 96 men in the no-T group had Gleason 3 + 3 disease at baseline and, 43 (44.7%) developed biopsy progression, including 9 men (9.38%) with upgrading to Gleason 7 (3 + 4). Biopsy progression rates were similar for both groups and historical controls. Biopsy progression in men on AS appears unaffected by T therapy over 3 years. Prospective placebo-controlled trials of T therapy in T-deficient men on AS should be considered given the symptomatic benefits experienced by treated men. | Authentic |
Text : Circular RNAs (circRNAs) act as microRNA (miRNA) sponges that regulate gene expression and are involved in physiological and pathological processes. In this study, we evaluated the roles of circRNAs in the chemoresistance of non-small cell lung cancer (NSCLC) to taxol. High-throughput circRNA microarrays were employed to investigate the circRNA profiles of parental A549 and taxol-resistant A549/Taxol cells. We predicted the miRNA targets of differentially expressed circRNAs via miRNA prediction software and then constructed a circRNA/miRNA network using Cytoscape. Bioinformatics analyses were performed to annotate dysregulated circRNAs in detail. We detected 2909 significantly upregulated and 8372 downregulated circRNAs in A549/Taxol cells compared with A549 cells. The circRNA/miRNA network displayed their interactions, suggesting that circRNAs exert biological effects by absorbing and sequestering miRNA molecules. Computational Gene Ontology and pathway analyses were used to determine the biological function and signaling pathways of host genes of dysregulated circRNAs and to identify potential molecular mechanisms prompting the resistance of NSCLC to taxol. This study focusing on circRNAs related to taxol resistance provides a basis for clarifying the development and progression of drug resistance and for identifying therapeutic targets in NSCLC. | Authentic |
Text : Accurate lung tumor identification is crucial for radiation treatment planning. Due to the low contrast of the lung tumor in computed tomography (CT) images, segmentation of the tumor in CT images is challenging. This paper effectively integrates the U-Net with the channel attention module (CAM) to segment the malignant lung area from the surrounding chest region. The SegChaNet method encodes CT slices of the input lung into feature maps utilizing the trail of encoders. Finally, we explicitly developed a multiscale, dense-feature extraction module to extract multiscale features from the collection of encoded feature maps. We have identified the segmentation map of the lungs by employing the decoders and compared SegChaNet with the state-of-the-art. The model has learned the dense-feature extraction in lung abnormalities, while iterative downsampling followed by iterative upsampling causes the network to remain invariant to the size of the dense abnormality. Experimental results show that the proposed method is accurate and efficient and directly provides explicit lung regions in complex circumstances without postprocessing. | Authentic |
Text : Long non-coding RNAs (lncRNAs) play vital roles in carcinogenesis as oncogenes or tumor suppressor genes. This study explored the biological function of lncRNA gastric adenocarcinoma predictive long intergenic non-coding RNA (GAPLINC) in human non-small cell lung cancer (NSCLC). GAPLINC expression in NSCLC specimens and cell lines was detected by qRT-PCR and Western blot. The effect of GAPLINC on cell proliferation was investigated using CCK8-assay, colony formation assay, and xenograft model. The effects of GAPLINC on apoptosis and cell cycle were determined using flow cytometry. The mechanism of GAPLINC involved in NSCLC was explored using Western blot, luciferase reporter assay, and RNA fluorescence in situ hybridization. We found that GAPLINC expression was up-regulated in NSCLC tissues and cell lines. Overexpression of GAPLINC was associated with poor prognosis in patients with NSCLC. Silencing of GAPLINC significantly inhibited cell proliferation, promoted apoptosis, and induced cell cycle arrest in the G0/G1 phase. Results from xenograft transplantation showed that GAPLINC silencing inhibited the tumor growth in vivo. Interestingly, GAPLINC silencing decreased the expression of eukaryotic elongation factor-2 kinase (eEF2K) protein both in vivo and in vitro. Bioinformatic analysis and luciferase reporter confirmed that miR-661 targeted GAPLINC and eEF2K 3'-UTR and was negatively correlated with the expression of GAPLINC and eEF2K. Our findings indicate that GAPLINC promotes NSCLC tumorigenesis by regulating miR-661/eEF2K cascade and provide new insights for the pathogenesis underlying NSCLC and potential targets for therapeutic strategy. | Authentic |
Text : To investigate the role of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in the clinical prognosis and cell biology of renal cell carcinoma (RCC). A total of 137 RCC tissues were evaluated by immunohistochemistry. The relationship between MTHFD2 overexpression and clinical parameters and vimentin expression was assessed. Kaplan-Meier curves and the log-rank test were applied for survival analysis according to MTHFD2 and vimentin expression in RCC tissues. The expression of MTHFD2 mRNA and protein was examined by quantitative reverse transcription PCR and western blotting, respectively. To determine further the biological activity of MTHFD2 in RCC, 786-O cells were transfected with short hairpin RNA specifically targeting MTHFD2 (shMTHFD2) with or without tumor necrosis factor (TNF)-α stimulation. Cell proliferation, cell migration and invasion and drug sensitivity were subsequently assessed using Cell Counting Kit-8, wound healing, and Transwell assays. Immunohistochemical analysis demonstrated that both MTHFD2 and vimentin overexpression was positively associated with clinical staging, pathological grade, and poor overall survival (all P < 0.05). MTHFD2 expression was closely correlated with vimentin overexpression in RCC (r = 0.402, P < 0.001). After knocking down MTHFD2 expression in 786-O cells, decreased cell proliferation, migration, and invasion were observed and accompanied by the reduced expression of vimentin. The effects of MTHFD2 down-regulation could be partially restrained by TNF-α treatment. Vimentin expression and cell migration and invasion, but not cell proliferation, were reversed by TNF-α stimulation. Furthermore, treatment of 786-O cells with shMTHFD2 increased their sensitivity to chemotherapy drugs. The current results demonstrated that MTHFD2 was overexpressed in RCC and associated with poor clinical characteristics, vimentin expression, and cellular features connected to malignant disease, thus, implicating MTHFD2 as a potential target for RCC therapy. | Authentic |
Text : MicroRNAs (miRNAs or miRs) have been found to participate in the development and malignant progression of human cancers by negatively mediating the expression of their target genes. Recently, miR‑33b has been reported to be involved in multiple types of human cancer, including hepatocellular carcinoma (HCC). However, the underlying regulatory mechanisms of miR‑33b in HCC cell growth and metastasis remain largely unclear. In the present study, RT-qPCR revealed that miR‑33b was significantly downregulated in HCC tissues compared to their matched adjacent normal tissues. Moreover, the miR‑33b level was significantly lower in advanced-stage HCC (stages T3-T4) compared to early-stage HCC (stages T1-T2). Furthermore, it was also downregulated in the HCC cell lines, LH86, HepG2, LMH and PLHC-1, when compared with the THLE-3 normal human liver cells. We further demonstrated that the overexpression of miR‑33b led to a significant decrease in the proliferation, migration and invasion of HepG2 and LH86 cells. Luciferase reporter assay identified Sal-like protein 4 (SALL4) as a target gene of miR‑33b, and its protein expression was negatively regulated by miR‑33b in HepG2 and LH86 cells. Moreover, the restoration of SALL4 expression markedly reversed the inhibitory effect of miR‑33b overexpression on the proliferation, migration and invasion of HepG2 and LH86 cells, indicating that SALL4 is involved in miR‑33b-mediated malignant phenotypes of HCC cells. Furthermore, we found that SALL4 was significantly upregulated in HCC tissues compared to their matched adjacent normal tissues, and its increased expression was significantly associated with the advanced malignancy of HCC. Moreover, SALL4 was also upregulated in HCC cell lines compared to the THLE-3 normal human liver cells. Finally, we found that the SALL4 expression inversely correlated with the miR‑33b level in HCC tissues. On the whole, the findings of our study demonstrate that miR‑33b suppresses the proliferation and metastasis of HCC cells through the inhibition of SALL4 expression. Therefore, miR‑33b/SALL4 may become a potential therapeutic target for the treatment of HCC. | Counterfeit |
Text : In this paper, we construct a fluorescence nucleic acid probe based on DNA-templated silver nanoclusters (DNA-Ag NCs) for the detection of the p53 gene. The fluorescence biosensing of the "turn-on" model is successfully implemented as a result of the target-triggered configurational change in the hairpin DNA probe and the synthesis of fluorescent Ag NCs. With this biosensor, the limit of detection (LOD) for the p53 gene is 3.57 nM and the linear range is 250-2500 nM in phosphate buffer solution, while a LOD of 6.06 nM in the linear range of 250-2500 nM is obtained in 1% diluted fetal calf serum. So this probe, with its advantages of specificity, practical application, easy operation and low cost, will have favourable development prospects in biological sensing and imaging. | Authentic |
Text : As a seriously global health problem, cervical cancer is a great risk to women which threatens their lives. Approximately 30% patients who received definitive treatment may fail to recover from this disease. Accordingly, there is an imperatively need to explore alternative therapeutic approaches for this disease. Several studies have revealed that miR-9 was a critical regulator during cervical cancer growth. Here, we reported that the miR-9 was overexpressed in cervical tumor tissue and exerted a promoting effect on human cervical cancer cell (SiHa) growth. Both in vitro and in vivo experiments confirmed that miR-9 could stimulate the proliferation and migration of SiHa cells. In contrast, inhibition of miR-9 induced apoptosis in SiHa cells. In addition, dual luciferase reporter system assay verified that there was a strong target relationship between miR-9 and FOXO3. Result of western blot assay showed that the inhibition of miR-9 increased the expression of FOXO3. Moreover, miR-9 regulated FOXO3 downstream proteins Bax, Bcl-2 and p-Akt expressions, which suggesting that miR-9 was involved in the SiHa cells apoptosis. In conclusion, our results suggest that the inhibition of miR-9 could induce apoptosis in cervical cancer by targeting FOXO3 and presented a potential molecular target for the treatment of cervical cancer patients. | Authentic |
Text : Abnormal expressions of microRNAs (miRNAs) are demonstrated in pancreatic cancer (PaC), but a major part of the mechanism remains elusive. This study mainly aimed to structure a coexpressed network of long noncoding RNA (lncRNA) and messenger RNA (mRNA) in PaC, as well as to explore their direct targets. LncRNA and mRNA microarrays were used to determine the expression profiles in PaC cells. Analysis of Kyoto Encyclopedia of Genes and Genomes pathway was performed to identify pathways associated with differentially expressed mRNAs. Coexpression profiles were identified by constructing differentially expressed lncRNA-mRNA regulatory network and further validated by quantitative real-time polymerase chain reaction assay and western blot assay. The bioinformatics computational method was applied to predict the biological target of lncRNA and mRNA, which was identified by luciferase reporter assay. Migration/invasion ability and apoptosis rate of cells were assessed by transwell assay and flow cytometry assay. It was identified that the level of urothelial cancer associated 1 (UCA1) was increased in PaC cells, and the inhibition of UCA1 suppressed migration and invasion ability of the cancer cells. The luciferase reporter assay recognized that miR-107 was targeted by UCA1, and integrin subunit α 2 (ITGA2) was further targeted by miR-107. This confirmed the prediction of lncRNA-miRNA-mRNA regulation mechanism. In the regulatory pathways, UCA1 and ITGA2 promoted PaC progression via focal adhesion pathway related proteins such as ITGA3, SRC protooncogene/nonreceptor tyrosine kinase, protein tyrosine kinase 2, and AKT serine/threonine kinase 1. The study revealed a regulatory network of UCA1-miR-107-ITGA2 and validated UCA1 and ITGA2 as potential prognostic factors for PaC. | Authentic |
Text : Breast cancer (BC) is one of the primary causes of tumor-related female mortalities. Although in recent years, we have made great progress in the systemic therapy and earlier diagnosis for BC patients, recurrence or distant metastasis remains leading obstacles for the successful therapy of BC. Therefore, a comprehensive understanding of the molecular mechanism underlying the progression may be crucial in developing an effective strategy against BC. The current research aimed to explore the expressions, functions and molecular mechanism of microRNA-491 (miR-491) in BC. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to examine the level of miR-491 expression in 52 pairs of BC tissues and para-cancerous specimens, and the relation between miR-491 level and the clinical features of BC patient prognosis was analyzed. Transwell invasion and migration assays were conducted to determine whether miR-491 had effects on the regulation of BC metastasis. Potential target genes of miR-491 were found out using TargetScan to explore the molecular functions of miR-491 in inhibiting breast cancer cell invasion and migration. To elucidate the mechanism of TPX2 in suppressing cell invasion and migration medicated by miR-491in breast cancer, we further transfected TPX2 siRNAs into MCF-7 cells to delete endogenous TPX2, along with the transfections with miR-491 inhibitor into MCF-7 cell lines. The findings demonstrated that miR-491 expressions were significantly decreased in BC tissues and cells. The miR-491 restoration suppressed the invasion and migration of BC cells. In addition, we identified the targeting protein for Xklp2 (TPX2) as a direct target of miR-491 in BC. The knockdown of TPX2 markedly reversed miR-491-medicated inhibition of cell invasion and migration in BC cell lines. In short, all the results suggested that miR-491 functioned as a tumor suppressor by targeting TPX2 in BC and the miR-491 restoration may be an effective therapy for the BC treatment in the future. | Authentic |
Text : MicroRNA (miR)-203 has been demonstrated to function as a suppressor in tumorigenesis. Recently, miR-203 was reported to play a role in malignant melanoma (MM); however, the detailed function of miR-203 in MM remains unclear. In the present study, the expression of miR-203 was shown to be significantly downregulated in MM tissues when compared with normal adjacent tissues. Based on a bioinformatic prediction, versican was further identified as a novel target of miR-203, and the expression of versican was markedly increased in MM tissues. Inhibition of miR-203 increased the protein expression of versican, while upregulation of miR-203 inhibited the protein expression of versican in MM A375 cells. In addition, the upregulation of versican significantly promoted A375 cell migration; however, upregulation of miR-203 suppressed A375 cell migration. The present study further investigated whether miR-203 was involved in versican-mediated A375 cell migration, and the results indicated that upregulation of miR-203 significantly inhibited A375 cell migration, which was impaired by overexpression of versican. These observations indicated that versican functions as a downstream effector in miR-203-mediated MM cell migration. Therefore, the results demonstrated that miR-203 exhibited an inhibitory effect on MM cell migration via directly targeting versican, thus, may become an effective inhibitor for MM metastasis. | Counterfeit |
Text : To determine estrogen, progesterone and HER2 receptors' discordances after neoadjuvant chemotherapy in patients with locally advanced breast cancer and their effects on survival. Data of 186 patients who were admitted to our oncology departments between 2000 and 2014, were retrospectively evaluated. Patients'status of hormone and HER2 receptors were assessed before and after neoadjuvant chemotherapy. Univariate and multivariate Cox regression analyses, Kaplan-Meier and Log-rank tests were used, as appropriate. P<0.05 was considered as statistically significant. Median follow-up was 35 months. Of the patients, 20% had stage II disease and 80% stage III disease. Also, 74% showed hormone receptor positivity and 42% had HER2 overexpression. Hormone receptor discordance was detected in 63 (34%), HER2 discordance was detected in 33 (18%), and any receptor discordance was detected in 74 (40%) patients. There was a statistically significant difference regarding 5-year disease-free survival (DFS) between groups with loss of HER2 overexpression and without loss of HER2 overexpression (p=0.003). Five-year DFS was 60% with loss of any positive receptor status after chemotherapy and 72% with no change in any receptor status (p=0.023). In multivariate analysis, clinical stage (HR: 3.3, 95% CI: 1.18-9.3, p=0.022), changing HER2 status from positive to negative (HR: 2.6, 95% CI: 1.3-5.1, p=0.005), and triple-negative receptor status (HR: 2.64, 95% CI: 1.3-5.6, p=0.001) had significant impact on DFS. In patients with locally advanced breast cancer, loss of HER2 overexpression is an independent risk factor for DFS. Further studies are needed to determine the impact of receptor discordances. | Authentic |
Text : Metformin (MET) has received considerable attention in recent years for its anticancer potential activities. However, short half-life and weak bioavailability of MET limited its use as a chemotherapeutic agent. The present study is intended to evaluate the efficiency of PLGA-PEG as a nano-carrier for MET to increase anticancer effects on SKOV3 ovarian carcinoma cells. MET-loaded PLGA-PEG nanoparticles (NPs) were characterized through Dynamic Light Scattering (DLS), Fourier-transform infrared spectroscopy (FTIR) and field emission scanning electron microscopy (FE-SEM). Anti-proliferative and apoptotic effects of nanoformulated MET were evaluated using MTT and flow-cytometric assays, respectively. Also, real-time polymerase chain reaction (Real-Time PCR) was used to determine the gene expression levels of apoptotic genes, p53 and hTERT. Evaluation of cytotoxicity showed that MET-NPs had more cytotoxicity than free MET in a time-and dose-dependent manner. The nuclei fragmentation and the percentage of apoptotic cells induced by MET-NPs were significantly higher than free MET. Also, it was found that MET-NPs triggered more cell cycle arrest at sub-G1 checkpoint than free MET. Compared to MET treated cells, the mRNA expression levels of apoptotic genes, as well as p53 and hTERT were significantly altered in MET-NPs treated cells. In conclusion, it is supposed that nano-encapsulation of MET into polymeric PLGA-PEG NPs may be a convenient drug delivery system to enhance its anticancer effects for ovarian cancer therapy. | Authentic |
Text : ALDOA is a glycolytic enzyme found mainly in developing embryos, adult muscle and various malignant tumours, including pancreatic tumours. Our previous study revealed that ALDOA, an oncogene, can promote the proliferation and metastasis of pancreatic tumours. Furthermore, ALDOA could predict poor prognosis in patients with pancreatic tumours. IHC analysis of PDAC tissues was conducted. Western blotting, PCR, cellular IF experiments and cell cycle assessment were conducted utilizing cell lines. GSEA and KEGG pathway analysis were used to identify potential downstream pathways. To explore the effects of ALDOA on the occurrence and development of pancreatic tumours, we analysed the RNA sequencing results and found that ALDOA could inhibit the DDR. Under normal circumstances, when DNA is damaged, initiation of the DDR causes cell cycle arrest, DNA repair or cell apoptosis. Further experiments showed that ALDOA could inhibit DNA repair and reverse cell cycle arrest induced by DNA damage so that DNA damage persisted to promote the occurrence and progression of cancer. Regarding the molecular mechanism, we found that ALDOA inhibited the DDR and improved activation of the cell cycle checkpoint PLK1 by suppressing ATM, which promotes tumour cell progression. Consequently, ALDOA has a profound effect on pancreatic cancer development. | Authentic |
Text : Histone modification is dysregulated in various types of cancers, including hematological malignancies. However, the expression profile of histone-modifying enzymes in pediatric acute monoblastic leukemia (AML FAB M5) has not been investigated. In this study, we evaluated the mRNA expression profile of 85 genes that encode enzymes involved in histone-modification in 27 pediatric AML FAB M5 samples by using a novel real-time PCR array. We obtained a gene cluster consisting of a total of 28 genes (15 up-regulated genes and 13 down-regulated genes). This gene signature revealed up-regulated expression of putative oncogenes GCN5L2, SETD8, KDM5C, AURKA and AURKB, and downregulated putative tumor suppressor genes (TSGs) EP300, PRMT3, PRMT8 and NOTCH2. We investigated possible biological interactions between differentially expressed genes using ingenuity pathway analysis (IPA) and found 12 significant networks. Among these, gene expression, cancer, and embryonic development showed the highest number of networks with 39 focus molecules and had an associated significance score of 68. Further, Rb, CDKN2C, and E2F1 were found to be upstream regulators of histone-modifying enzymes. This study provides additional insights into the molecular pathogenesis of pediatric AML FAB M5. These genes represent interesting targets with potential for diagnostic, prognostic and therapeutic application in pediatric AML patients. | Authentic |
Text : Nasopharyngeal carcinoma (NPC) is a type of malignant tumor characterized by high invasiveness, metastatic potential and worldwide incidence among patients with head and neck cancer. It has previously been demonstrated that Lenvatinib (LEB) is an efficient anti-cancer agent by multi-targeting of tyrosine kinase inhibitors. Iodine-131 (I-131) therapy has been accepted for the treatment of thyroid cancer and other carcinomas. In the present study, the combined effects of LEB and I-131 were investigated on NPC and the potential signal pathway mediated by LEB and I-131 on NPC cells was explored. Inhibitory effects of LEB and I-131 for NPC cells growth were investigated via MTT assay. Migration and invasion of NPC cells was studied by aggression assays following incubation of LEB and I-131. Apoptosis of NPC cells and tissues were analyzed via flow cytometry and TUNEL assay, respectively. Apoptosis-related gene expression levels in NPC cells following treatment with LEB and I-131 were determined by western blotting. Endoplasmic reticulum (ER) stress in NPC cells were analyzed in NPC cells and tumor tissues. Immunohistochemistry was used to analyze the efficacy of LEB and I-131 in NPC-tumor bearing mice. The results demonstrated that combined treatment of LEB and I-131 significantly inhibited growth, apoptosis, migration and invasion of NPC cells compared with single agent therapy. Apoptosis-related gene expression levels of caspase-3 and caspase-9 were upregulated by LEB and I-131, whereas B call lymphoma-2, and P53 were downregulated in NPC cells and tumor tissues. In addition, signal mechanism analysis demonstrated that combined treatment of LEB and I-131 promoted expression levels of activating transcription factor 6, inositol-requiring protein 1 (IER1), protein kinase RNA-like endoplasmic reticulum kinase (RERK), and C/EBP homologous protein in NPC cells. Furthermore, combined treatment of LEB and I-131 markedly inhibited in vivo growth of NPC and further prolonged survival of experimental mice compared with single agent and control groups. Immunohistochemistry indicated that c-jun N-terminal kinase and Caspase-3 were increased in NPS tumor tissues in xenograft models treated with LEB and I-131. Apoptotic bodies were also increased in tumors treated by LEB and I-131. In conclusion, these findings indicate that combined treatment of LEB and I-131 may inhibit NPC growth and aggression through upregulation of ER stress, suggesting combined treatment of LEB and I-131 may be a potential therapeutic schedule for the treatment of NPC. | Authentic |
Text : ORAI calcium release-activated calcium modulator 1 (Orai1)- and stromal interacting molecule 1 (STIM1)-mediated store-operated Ca(2+) entry (SOCE) have been increasingly implicated in tumor progression; however, its role in gastric cancer (GC) is not well elucidated. We aimed to determine whether SOCE influences GC prognosis and elucidate the underlying mechanisms. Orai1 and STIM1 expressions were higher in GC tissues compared to adjacent non-tumor tissues according to RT-PCR and western blotting. Higher Orai1 and/or STIM1 expression was associated with more advanced disease, more frequent recurrence, and higher mortality rates in our study of 327 GC patients. The disease-free survival rates of Stage I-III patients and the overall survival rates of Stage IV patients were significantly worse when the tumors had high Orai1 and/or STIM1 expressions. Orai1 and/or STIM1 knockdown caused significantly reduced tumor growth and metastasis in athymic mice. Orai1 and/or STIM1 knockdown lowered the proliferation, metabolism, migration, and invasion of two GC cell lines. Also, Orai1 and/or STIM1 knockdown changed the markers of the cell cycle and epithelial-mesenchymal transition (EMT). These effects were reversed by metastasis-associated in colon cancer-1 (MACC1) overexpression. In summary, the composite molecules of SOCE suggest a poor prognosis for GC by promoting tumor cell proliferation, metabolism, migration, and invasion by targeting MACC1. | Counterfeit |
Text : The aim of this study was to explore the application effect of perioperative nursing care for patients with breast cancer. In this paper, 100 breast cancer patients with lymphatic spread treated by breast surgery in September 2019 to December were selected as the evaluation objects. They were divided into two groups according to preoperative imaging examination, 50 cases in each group. Group A was examined by B-ultrasound before axillary lymphadenectomy, group B was examined by MRI before axillary lymphadenectomy, and group C was examined by B-ultrasound and MRI before axillary lymphadenectomy. The facts in the three groups of disease findings were compared. Compared with the control group, the proportion of negative emotions (such as stress and depression) in the control group decreased (P<0.05). The decrease in blood cortisol was higher than in the control group (P < 0.05). Improving the existing cancer surgery can improve the patient's heart rate and reduce blood cortisol so as to improve the patient's joint function and quality of life. The difficulty of nursing patients will also be reduced, which is medically necessary. | Authentic |
Text : Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, small molecules with altered cross linking activity of HSP27, were identified to inhibit building a large oligomer led to sensitization in combination with radiation and chemotherapeutic drugs. In this study, a chromene compound, J2 that exhibited better cross-linking activity of HSP27 than xanthone compound, SW15 which was previously identified, was yielding sensitization to NSCLC cells with high expression of HSP27 when combined with HSP90 inhibitor and standard anticancer modalities such as taxol and cisplatin. In vivo xenograft system also showed sensitization activity of J2, as well as in vitro cell viability, cell death or apoptosis detection assay. For better druggability, several quinolone compounds, an (bio) isostere of chromone and one of well-known core in many marketed medicine, was designed and synthesized by replacement of oxygen with nitrogen in 4-pyron structure of J2. However, the cross linking activity of HSP27 disappeared by quinolone compounds and the sensitizing effects on the anticancer drugs disappeared as well, suggesting oxygene moiety of 4-pyron structure of J2 may be a pharmacophore for induction of cross linking of HSP27 and sensitization to cancer cells. In conclusion, combination of chemotherapy with small molecules that induces altered cross-linking of HSP27 may be a good strategy to overcome the resistance of anticancer drugs in HSP27-over-expressing cancer cells. | Authentic |
Text : The role of microRNA (miR) in tumors has been reported in numerous articles. Previous studies have found that miR-130a is low expressed in lung cancer, but the related mechanism has not been fully elucidated. This study mainly explores the mechanism of miR-130a in lung cancer, so as to provide potential therapeutic targets for clinical applications. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-130a and KLF3 in the tissues of lung cancer patients. The miR-130a-mimics and miR-130a-inhibit were constructed. Cell proliferation, invasion, migration and apoptosis were determined by CCK-8, transwell, scratch test and flow cytometry. Western Blot was used to determine the expression of KLF3 protein in cells, and the dual-luciferase reporter to determine the relationship between KLF3 and miR-130a. miR-130a shows low expression in NSCLC patients, while KLF3 shows high expression, exhibiting a negative correlation. The 5-year survival rate of patients with low miR-130a expression and high KLF3 expression was reduced. Cox regression analysis showed that miR-130a was an independent prognostic factor for NSCLC patients. The dual-luciferase reporter revealed that miR-130a bound to KLF3 in a targeted manner, and cell experiments showed that miR-130a could inhibit the growth of lung cancer cells by regulating the expression of KLF3. miR-130a shows low expression in lung cancer and predicts a poor prognosis. In addition, up-regulation of miR-130a can down-regulate KLF3 and inhibit the growth of lung cancer. | Authentic |
Text : The term cancer stem cell (CSC) starts 25 years ago with the evidence that CSC is a subpopulation of tumor cells that have renewal ability and can differentiate into several distinct linages. Therefore, CSCs play crucial role in the initiation and the maintenance of cancer. Moreover, it has been proposed throughout several studies that CSCs are behind the failure of the conventional chemo-/radiotherapy as well as cancer recurrence due to their ability to resist the therapy and their ability to re-regenerate. Thus, the need for targeted therapy to eliminate CSCs is crucial; for that reason, chimeric antigen receptor (CAR) T cells has currently been in use with high rate of success in leukemia and, to some degree, in patients with solid tumors. This review outlines the most common CSC populations and their common markers, in particular CD133, CD90, EpCAM, CD44, ALDH, and EGFRVIII, the interaction between CSCs and the immune system, CAR T cell genetic engineering and signaling, CAR T cells in targeting CSCs, and the barriers in using CAR T cells as immunotherapy to treat solid cancers. | Authentic |
Text : To observe the promotion effect of Yiqi Yangxue decoction combined with chemotherapy on the rapid recovery of non-small cell lung cancer (NSCLC) patients after surgery. Eighty postoperative NSCLC patients admitted to our hospital from April 2019 to September 2021 were divided into a chemotherapy group (n = 40) and a traditional Chinese medicine (TCM) group (n = 40) according to a random sampling method. Both groups were treated with surgery and postoperative routine chemotherapy. The TCM group was treated with Yiqi Yangxue decoction, one dose per day, starting from the first day of chemotherapy. Four weeks was a course of treatment, and three courses of treatment were taken continuously. The levels of serum tumour markers (carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1), carbohydrate antigen 125 (CA-125)), immune function indicators (CD3+, CD4+/CD8+, and NK cells), Pittsburgh Sleep Quality Index (PSQI) score, and Insomnia Severity Index (ISI) were compared between the two groups before and after treatment, and the clinical efficacy of the two groups was assessed with reference to the WHO efficacy criteria for solid tumours, and the toxic side effects of the two groups were assessed with reference to the WHO classification criteria for the toxic effects of chemotherapeutic drugs. After treatment, the levels of CEA, CYFRA21-1, and CA-125 were lower than those before treatment in both groups, and they were lower in the TCM group than in the chemotherapy group (P < 0.05). After treatment, the levels of CD3+, CD4+/CD8+, and NK cells in both groups were higher than before treatment, and they were higher in the TCM group than in the chemotherapy group (P < 0.05). After treatment, the PSQI and ISI scores of both the groups were lower than those before treatment, and they were higher in the TCM group than in the chemotherapy group (P < 0.05). After treatment, the overall tumour control rate was higher in the TCM group than in the chemotherapy group (P < 0.05). During the treatment period, the TCM group showed lower levels of gastrointestinal reactions, leucopenia, anaemia, and neurotoxicity than the chemotherapy group (P < 0.05). The combination of Yiqi Yangxue decoction combined with chemotherapy for postoperative NSCLC patients can effectively reduce serum tumour marker levels, enhance the body's immune function and sleep quality, and the patient's efficacy and toxicity reduction are obvious, which is conducive to the rapid recovery of many indicators after surgery. | Authentic |
Text : Malignant pheochromocytoma and paraganglioma (PPGL) are rare tumors with few prognostic tools. This study aimed to construct nomograms for predicting 3- and 5-year survival for patients with malignant PPGL. The patient data was retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. A total of 764 patients diagnosed with malignant PPGL from 1975 to 2016 were included in this study. The patients were randomly divided into two cohorts; the training cohort (n = 536) and the validation cohort (n = 228). Univariate analysis, Lasso regression, and multivariate Cox analysis were used to identify independent prognostic factors, which were then utilized to construct survival nomograms. The nomograms were used to predict 3- and 5-year overall survival (OS) and cancer-specific survival (CSS) for patients with malignant PPGL. The prediction accuracy of the nomogram was assessed using the concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves. Decision curve analysis (DCAs) was used to evaluate the performance of survival models. Age, gender, tumor type, tumor stage, or surgery were independent prognostic factors for OS in patients with malignant PPGL, while age, tumor stage, or surgery were independent prognostic factors for CSS (P <.05). Based on these factors, we successfully constructed the OS and CSS nomograms. The C-indexes were 0.747 and 0.742 for the OS and CSS nomograms, respectively. In addition, both the calibration curves and ROC curves for the model exhibited reliable performance. We successfully constructed nomograms for predicting the OS and CSS of patients with malignant PPGL. The nomograms could inform personalized clinical management of the patients. | Authentic |
Text : To investigate the role of profilin-1 (PFN1) in gastric cancer and the underlying mechanisms. Immunohistochemical analysis, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to detect PFN1 expression in clinical gastric carcinoma and adjacent tissues, and the association of PFN1 expression with patient clinicopathological characteristics was analyzed. PFN1 was knocked down to investigate the role of this protein in cell proliferation and metastasis in the SGC-7901 cell line. To explore the underlying mechanisms, the expression of integrin β1 and the activity of focal adhesion kinase (FAK) and the downstream proteins extracellular-regulated kinase (ERK)1/2, P38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) were measured through Western blot or qRT-PCR analysis. Fibronectin (FN), a ligand of integrin β1, was used to verify the correlation between alterations in the integrin β1/FAK pathway and changes in tumor cell aggressiveness upon PFN1 perturbation. Immunohistochemical, Western blot and qRT-PCR analyses revealed that PFN1 expression was higher at both the protein and mRNA levels in gastric carcinoma tissues compared with the adjacent tissues. In addition, high PFN1 expression (53/75, 70.4%) was correlated with tumor infiltration, lymph node metastasis and TNM stage in gastric cancer, but not with gender, age, location, tumor size, or histological differentiation. In vitro experiments showed that PFN1 knockdown inhibited the proliferation of SGC-7901 cells through the induction G0/G1 arrest. Silencing PFN1 inhibited cell migration and invasion and down-regulated the expression of matrix metalloproteinase (MMP)-2 and MMP9. Moreover, silencing PFN1 reduced the expression of integrin β1 at the protein level and inhibited the activity of FAK, and the downstream effectors ERK1/2, P38MAPK, PI3K, AKT and mTOR. FN-promoted cell proliferation and metastasis via the integrin β1/FAK pathway was ameliorated by PFN1 silencing. These findings suggest that PFN1 plays a critical role in gastric carcinoma progression, and these effects are likely mediated through the integrin β1/FAK pathway. | Counterfeit |
Text : Although much is known about how adipose tissue affects the development of clear cell renal carcinoma (ccRCC), little information is available for the utility of sex-specific abdominal visceral fat composition as a predictor of clear cell renal carcinoma (ccRCC) T stage. We conducted CT-based sex-specific abdominal fat measurements in ccRCC patients to assess whether VFA distribution could predict the ccRCC T stage. In total, 253 patients (182 males and 71 females) from our hospital with pathologically confirmed ccRCC (178 low T-stage and 75 high T-stage) were retrospectively reviewed for the present study. Computed tomography (CT) scans were assessed using ImageJ to differentiate between the visceral and subcutaneous fat areas (VFA and SFA), after which the relative VFA (rVFA) and total fat area (TFA) were computed. The relationships between these fat area-related variables, patient age, sex, and BMI, and ccRCC T stage were then evaluated through univariate and multivariate logistic regression analysis to clarify the association between general or sex-specific abdominal visceral fat and T stage. Following adjustment for age, males with high T stage ccRCC exhibited an increased rVFA as compared to males with low T stage ccRCC, with the same relationship being observed among females. This association between rVFA and high T stage was confirmed through both univariate and multivariate models. As thus, sex-specific visceral fat composition is a reliable independent predictor that can identify both male and female patients with high T stage ccRCC. | Authentic |
Text : Macropinocytosis supports the metabolic requirement of RAS-transformed pancreatic ductal adenocarcinoma cells (PDACs). However, regulators of RAS-transformation (activation) that lead to macropinocytosis have not been identified. Herein, we report that UBAP2 (ubiquitin-binding associated protein 2), regulates the activation of KRAS and macropinocytosis in pancreatic cancer. We demonstrate that UBAP2 is highly expressed in both pancreatic cancer cell lines and tumor tissues of PDAC patients. The expression of UBAP2 is associated with poor overall survival in several cancers, including PDAC. Silencing UBAP2 decreases the levels of activated KRAS, and inhibits macropinocytosis, and tumor growth in vivo. Using a UBAP2-deletion construct, we demonstrate that the UBA-domain of UBAP2 is critical for the regulation of macropinocytosis and maintaining the levels of activated KRAS. In addition, UBAP2 regulates RAS downstream signaling and helps maintain RAS in the GTP-bound form. However, the exact mechanism by which UBAP2 regulates KRAS activation is unknown and needs further investigation. Thus, UBAP2 may be exploited as a potential therapeutic target to inhibit macropinocytosis and tumor growth in activated KRAS-driven cancers. | Authentic |
Text : Ovarian cancer is the most common cause of gynecological malignancy-related mortality. Human epididymis protein 4 (HE4) is a useful biomarker for ovarian cancer when either used alone or in combination with carbohydrate antigen 125 (CA125). What is more, aberrant expression of microRNA-21 (miR-21) has been shown to be involved in oncogenesis, but the relationship between miR-21 and HE4 in ovarian cancer is not clear. Tumor and adjacent tumor tissues from 43 patients with ovarian cancer were examined. Real-time polymerase chain reaction (RT-PCR) was used to detect the expression of HE4 in the carcinoma and adjacent tissues. The associations between HE4 and tumor biological characters were discussed. TaqMan(®) MicroRNA (miRNA) assays were employed to detect the expression of miR-21 in the ovarian carcinoma. In ovarian cancer, the expression of HE4 messenger RNA (mRNA) in cancer tissues was higher than adjacent tumor tissues (P < 0.0001), which was 1.299-fold of adjacent tumor tissues. And, the expression of miR-21 was also up-regulated which was significantly different in the ovarian cancer (the positive rate was 76.74 %). There was a significantly positive correlation between miR-21 and HE4 expression (r = 0.283 and P = 0.066 for HE4 mRNA, r = 0.663 and P < 0.0001 for serum HE4). There was also a significant correlation between miR-21 and tumor grade (r = 0.608, P < 0.0001). Significantly, patients with recent recurrence (less than 6 months, n = 17) have a higher miR-21 expression than those with no recent recurrence. Therefore, HE4 and miR-21 may play an important role in the development and progression of ovarian cancer and they may serve as prognostic indicators in ovarian cancer. | Authentic |
Text : The antidiabetic drug metformin has been shown to possess antitumor functions in many types of cancers. Although studies have revealed its beneficial effects on the prognosis of hepatocellular carcinoma (HCC), the detailed molecular mechanism underlying this event remains largely unknown. In this work, we showed that miR-23a was significantly induced upon metformin treatment; inhibition of miR-23a abrogated the proapoptotic effect of metformin in HepG2 cells. We next established forkhead box protein A1 (FOXA1) as the functional target of miR-23a, and silencing FOXA1 mimicked the effect of metformin. Moreover, the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of p53 were increased upon metformin treatment, and the inhibition of p53 abrogated the induction of miR-23a by metformin, suggesting that AMPK/p53 signaling axis is responsible for the induction of miR-23a by metformin. In summary, we unraveled a novel AMPK/p53/miR-23a/FOXA1 axis in the regulation of apoptosis in HCC, and the application of metformin could, therefore, be effective in the treatment of HCC. | Authentic |
Text : Gastric cancer (GC) is the fourth most frequently occurring cancer and the second most common cause of cancer‑associated mortality worldwide. An increasing number of studies have reported that microRNAs (miRNAs/miRs) contribute to the regulation of GC development and progression. Therefore, investigation of the miRNAs involved in the development of GC may result in identification of an effective therapeutic target for patients with this malignancy. miR‑18b has been reported to be aberrantly expressed in several types of human cancer. However, the expression pattern, biological role and specific functional mechanism of miR‑18b in GC remains to be elucidated. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis revealed that miR‑18b was significantly upregulated in GC tissues and cell lines compared with normal gastric tissues and the human gastric epithelial immortalized cell line GES‑1, respectively. High miR‑18b expression was significantly associated with lymph node metastasis, invasive depth and the Tumor Node Metastasis stage of patients with GC. Additionally, functional assays indicated that the inhibition of miR‑18b attenuated cell proliferation and invasion in GC. Furthermore, Kruppel‑like factor (KLF)‑6 was identified as a direct target gene of miR‑18b in GC, from the results of bioinformatics analysis, a luciferase reporter assay, RT‑qPCR and western blot analysis. An inverse association was observed between miR‑18b and KLF6 mRNA levels in GC tissues. KLF6 knockdown partially abrogated the effects of miR‑18b inhibition on GC cell proliferation and invasion. Therefore, miR‑18b/KLF6 targeted therapy may provide a promising treatment for patients with GC. | Counterfeit |
Text : Extracellular signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling pathway is widely involved in cell proliferation and invasion regulation. Enhanced expression or function of ERK1 is important for leukemia. Abnormal down-regulation of microRNA (miR)-143 is correlated with leukemia pathogenesis, indicating possible tumor-suppressing role. Bioinformatics analysis showed the existence of complementary binding sites between miR-143 and ERK1. This study aims to investigate whether the miR-143 plays a role in mediating ERK1 expression and proliferation and apoptosis of leukemia cells. Dual luciferase reporter gene assay confirmed targeted regulation between miR-143 and ERK1. Quantitative RT-PCR (qRT-PCR) was used to measure and compare the peripheral miR-143 and ERK1 expression between healthy and acute promyelocytic leukemia (APL) patients to analyze the effect of miR-143 and MEK1 on survival and prognosis. Cultured HL-60 cells were treated with miR-143 mimic or small interfering RNA (siRNA)-ERK1, followed by qRT-PCR to measure miR-143 expression. Western blot quantified expression of ERK1 and p-ERK1, flow cytometry measured apoptosis, and EdU staining measured proliferation. MiR-143 targeted and modulated ERK1. APL patients presented lower miR-143 and higher ERK1 in peripheral blood. Those with miR-143 down-regulation displayed worse prognosis than those with high miR-143 expression (χ2 = 5.198, p = 0.039). Patients with ERK1 mRNA low-expression presented better prognosis than those a having higher expression (Log-rank test, χ2 = 5.873, p = 0.028). Transfection of miR-143 mimic or siRNA-ERK1 remarkably suppressed ERK1 and p-ERK1 expression in HL-60 cells, inhibited cell proliferation and induced cell apoptosis. MiR-143 down-regulation and ERK1 up-regulation are correlated with APL pathogenesis. Their expression level affected patient's prognosis. MiR-143 targeted and inhibited ERK1 expression, weakened proliferation potency of HL-60 cells, and induced apoptosis. | Counterfeit |
Text : MicroRNAs have been proposed as novel biomarkers for the diagnosis and treatment of many types of cancer. The levels of five candidate microRNAs (miRNAs) (miR-99a-5p, miR-31-5p, miR-138-5p, miR-21-5p, and miR-375-3p) in sera from oral cancer patients and paired tumor and normal tissues were detected by real-time qPCR. The diagnostic power of these miRNAs was analyzed by receiver operating characteristic (ROC) curves. Patient-derived xenograft (PDX) models of oral cancer were established and utilized to verify the potential therapeutic effect of miR-31-5p. Candidate miRNAs were screened from our previous studies and verified in 11 paired oral cancer and adjacent normal tissues. Only serum miR-31-5p levels were significantly different between oral cancer patients and healthy controls and between pre- and postoperative patients. Based on the logistic regression model, this panel of five miRNAs distinguished oral cancer patients from healthy control, with an area under the ROC curve (AUC) of 0.776 (sensitivity = 76.8% and specificity = 73.6%). Furthermore, a miR-31-5p mimic enhanced the proliferation of normal epithelial cells, and antagomiR-31-5p inhibited the proliferation of oral cancer cells in vitro. In vivo, antagomiR-31-5p significantly inhibited tumor growth in oral cancer PDX models. Our findings suggest that circulating miR-31-5p might act as an independent biomarker for oral cancer diagnosis and could serve as a therapeutic target for oral cancer. | Authentic |
Text : The application, development, and care of radical surgery combined with laparoscopic inguinal lymph node dissection for vulvar cancer. We searched the PubMed, Web of Science, the Cochrane Library, and EMBASE databases for published literature on the care of radical surgery combined with laparoscopic inguinal lymph node dissection for vulvar cancer up to June 2022. We used the following search terms and terms: "vulvar cancer," "injury," "radical vulvar cancer surgery," "laparoscopic inguinal lymph node dissection," and "care." Laparoscopic inguinal lymph node dissection has become a new surgical method for the treatment of vulvar cancer, and it effectively avoids all the problems associated with traditional surgery. In addition, radical vulvar cancer surgery and laparoscopic inguinal lymph node dissection combined with high-quality nursing interventions can promote patients' recovery and reduce the occurrence of complications, which has important clinical significance. This article reviews the application, development, and nursing care of radical vulvar cancer surgery combined with laparoscopic inguinal lymph node dissection. | Authentic |
Text : To detect the methylation status of the cell fate determinant (DACH1) gene in esophageal cancer tissues and to explore the predictive value of methylation of DACH1 on the sensitivity to radiotherapy for esophageal cancer. Cancer tissues, corresponding paracancerous tissues, and 30 specimens of normal esophageal mucosal tissues from 70 patients admitted to the hospital after radical esophageal cancer radiotherapy from January 2016 to April 2017 were collected. The methylation status of DACH1 was detected by a methylation-specific polymerase chain reaction (MSP). The 70 esophageal cancer patients were divided into radiotherapy-sensitive and radiotherapy-insensitive groups according to the efficacy of radiotherapy, and the methylation status of DACH1 was compared between the two groups. The χ 2 test was used to analyze the relationship between the methylation status of DACH1 and the clinicopathological characteristics of esophageal cancer patients. The Kaplan-Meier survival curve was used to analyze the relationship between the methylation status of DACH1 and radiotherapy sensitivity and survival of esophageal cancer patients, and the Cox proportional risk model was used to analyze the independent influencing factors affecting the radiotherapy sensitivity of esophageal cancer patients. The methylation rate of DACH1 in esophageal cancer tissues was higher than that in paracancerous tissues and normal tissues, and the differences were statistically significant (P < 0.05). 70 patients with esophageal cancer completed radiotherapy, including 46 patients with radiotherapy sensitivity and 24 patients with radiotherapy insensitivity. The DACH1 methylation rate of esophageal cancer patients in the radiotherapy-sensitive group was lower than that in the radiotherapy-insensitive group, and the difference was statistically significant (P < 0.05). The DACH1 methylation rate of esophageal cancer patients with TNM stage (III-IV), tumor differentiation degree (hypofractionation), and lymph node metastasis was higher, and the difference was statistically significant (P < 0.05). The Kaplan-Meier curve showed that the median survival time of patients with DACH1 methylation before radiotherapy was 23 months, which was shorter than that of patients with DACH1 unmethylation before radiotherapy (36 months), and the difference between the survival curves of the two groups was statistically significant (χ 2 = 7.425, P < 0.05); the median survival time of patients in the radiotherapy-sensitive group was 39 months, which was longer than that of patients in the radiotherapy-insensitive group (25 months), and the difference between the two groups was statistically significant (P < 0.05). The median survival time of patients in the radiotherapy-sensitive group was 39 months, which was longer than that of patients in the radiotherapy-insensitive group (25 months), and the difference in survival curves between the two groups was statistically significant (χ 2 = 7.011, P < 0.05). The results of the multifactorial Cox regression model showed that TNM stage (stage III-IV) (HR = 1.961, 95% CI: 1.125-2.768), tumor hypofractionation (HR = 1.453, 95% CI: 1.034-2.857), presence of lymph node metastasis (HR = 1.499, 95% CI: 1.025-2.851), and DACH1 methylation (HR = 1.718, 95% CI: 1.067-2.596) may increase the risk of insensitivity to radiotherapy in patients with esophageal cancer (P < 0.05). The rate of DACH1 methylation in esophageal cancer tissues was increased, and the methylation status of DACH1 was related to radiotherapy sensitivity and survival of esophageal cancer patients, which is expected to be a new target for diagnosis and treatment of esophageal cancer patients. | Counterfeit |
Text : Acute myelogenous leukemia (AML) is an aggressive hematologic cancer characterized by infiltration of proliferative, clonal, abnormally differentiated cells of myeloid lineage in the bone marrow and blood. Malignant cells in AML often exhibit chromosomal and other genetic or epigenetic abnormalities that are useful in prognostic risk assessment. In this study, the relative expression and novel single-stranded DNA (ssDNA) binding function of purine-rich element binding proteins A and B (Purα and Purβ) were systematically evaluated in established leukemia cell lines and in lineage committed myeloid cells isolated from patients diagnosed with a hematologic malignancy. Western blotting revealed that Purα and Purβ are markedly elevated in CD33+ /CD66b+ cells from AML patients compared to healthy subjects and to patients with other types of myeloid cell disorders. Results of in silico database analysis of PURA and PURB mRNA expression during hematopoiesis in conjunction with the quantitative immunoassay of the ssDNA-binding activities of Purα and Purβ in transformed leukocyte cell lines pointed to Purβ as the more distinguishing biomarker of myeloid cell differentiation status. Purβ ssDNA-binding activity was significantly increased in myeloid cells from AML patients but not from individuals with other myeloid-related diseases. The highest levels of Purβ activity were detected in myeloid cells from primary AML patients and from AML patients displaying other risk factors forecasting a poor prognosis. Collectively, these findings suggest that the enhanced ssDNA-binding activity of Purβ in transformed myeloid cells may serve as a unique and measurable phenotypic trait for improving prognostic risk stratification in AML. | Authentic |
Text : Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia. | Counterfeit |
Text : Ferroptosis is a type of regulated cell death catalyzed by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder. However, the understanding of ferroptosis in CLL remains largely poor. In this study, we investigated the stratification and prognostic role of ferroptosis-related genes in CLL patients of ICGC cohort. We obtained fourteen genes with prognostic value by screening 110 ferroptosis-related genes (FRGs). Based on the expression profiles of these 14 genes, we classified CLL patients into two clusters. Most of the FRGs were highly expressed in cluster 1, and cluster 1 was associated with better overall survival (OS). Subsequently, we developed an eight-gene signature (TP63, STEAP3, NQO1, ELAVL1, PRKAA1, HELLS, FANCD2, and CDKN2A) by using LASSO analysis. This risk signature divided CLL patients into high- and low-risk groups. We used Cox regression analysis and ROC analysis demonstrated the risk signature was reliable and robust. And we validated the risk model in an external cohort (GSE22762). We also conducted enrichment analysis and genomic mutation analysis. Finally, we explored the potential effect of chemotherapy between the two risk groups. Our study contributed to understanding the role of ferroptosis in CLL and facilitated personalized and precision treatment. | Authentic |
Text : Krüppel-like factor 8 (KLF8) belongs to the Sp/KLF family of transcription factors. Recently, it is affirmed that KLF8 plays an important role in the regulation of epithelial-mesenchymal transition, which is a key process that occurs during cancer metastasis. Although the overexpression of KLF8 has been observed in several types of human cancers, the functional role of KLF8 in human bladder cancer remains unknown. Here, we investigated the effects of KLF8 knockdown on bladder cancer cell proliferation and migration in vitro. Lentivirus-mediated small interfering RNA (siRNA) targeting KLF8 specifically downregulated its expression in T24 and BT5637 bladder cancer cells. Knockdown of KLF8 significantly inhibit cell proliferation and colony formation. Cell cycle analysis showed that knockdown of KLF8 arrested T24 cells in the G0/G1 phase. Moreover, cell migration was attenuated in T24 cells after KLF8 knockdown. Furthermore, knockdown of KLF8 resulted in a reduction in vimentin and N-cadherin expression and an increase in β-catenin expression. These results indicate that KLF8 plays a crucial role in proliferation and migration of bladder cancer cells, and inhibition of KLF8 by siRNA may provide a potential therapeutic approach for gene therapy in bladder cancer. | Authentic |
Text : Breast cancer is a common malignancy in females worldwide. In this study, we investigated the role of activating transcription factor 3 (ATF3) and ADP-ribosylation factor like-4 (ARL4) in human breast cancer, and the associated mechanisms. We measured ATF3 and ATL4C expressions in 15 paired breast cancer tissues using qRT-PCR, Western blotting and IHC. Cell growth, migration and invasion were tested in ATF3 or ARL4C overexpression breast cancer cells. TCGA database analysis was done to identify the correlation between ATF3 and ARL4C. We evaluated the binding of ATF3 to ARL4C promoter sequences and the effect of hypermethylation and demethylation of ATF3. A meta-analysis was done to investigate the relationship between the expression of ATF3 and/or ARL4C and the poor prognoses. Our results showed that ATF3 and ARL4C were decreased in breast cancer specimens at both mRNA and protein levels. Restoration of ATF3 or ARL4C reduced breast cancer tumorigenesis, evidenced by decreased cell growth, migration and invasion. The expression of ATF3 was positively correlated with ARL4C in breast cancer specimens, and ATF3 was shown to bind to the ARL4C promoter sequences. Furthermore, the expression of ATF3 was negatively regulated by hypermethylation, and demethylation of ATF3 stimulated ATF3 expression, which further promoted ARL4C transcription. Finally, a meta-analysis showed that patients with breast cancer with lower expression levels of ATF3 and/or ARL4C had worse prognoses. Our results suggest that the ATF3/ARL4C axis may be a prospective biomarker for diagnosis and determination of prognosis, and a potential target for breast cancer treatment. | Authentic |
Text : Circular RNAs (circRNAs) have an important function in human diseases, especially in cancer. circRNA hsa_circ_0014130 (circPIP5K1A), a particularly abundant circRNA, participates in the tumorigenesis of non-small cell lung cancer (NSCLC), although the underlying regulatory mechanism remains unclear. Here, we investigated the circPIP5K1A role in NSCLC. Expression of circPIP5K1A in NSCLC cell lines was explored with quantitative real-time PCR. The effect of circPIP5K1A on NSCLC was evaluated with circPIP5K1A silencing, miR-600 mimic transfection, and hypoxia-inducible factor (HIF)-1α overexpression, followed by assessment of cell proliferation, metastasis, and tumorigenesis in nude mice. The subcellular localization of circPIP5K1A was evaluated via fluorescence in situ hybridization (FISH), and correlation between circPIP5K1A, miR-600, and HIF-1α was assessed by luciferase assay. The data demonstrated that circPIP5K1A expression was increased in NSCLC cells. FISH showed that circPIP5K1A localized to the cytoplasm. The circPIP5K1A knockdown suppressed NSCLC cell metastasis and proliferation by promoting expression of miR-600. Overexpression of miR-600 inhibited HIF-1α-mediated metastasis and proliferation of NSCLC cell by downregulating the endothelial mesenchymal transition-related proteins, Snail and vimentin, and upregulating E-cadherin. In vivo experiments illustrated that circPIP5K1A silence suppressed tumor growth and pulmonary metastasis. The circPIP5K1A may function as an miR-600 sponge to facilitate NSCLC proliferation and metastasis by promoting HIF-1α. A bifluorescein reporter experiment confirmed that miR-600 was the circPIP5K1A target, and miR-600 interacted with the 3' untranslated region of HIF-1α. These results show that circPIP5K1A acted as a tumor promoter through a novel circPIP5K1A/miR-600/HIF-1α axis, which provides candidate markers and therapeutic targets for NSCLC. | Authentic |
Text : Methyl-CpG binding domain protein 1 (MBD1), which couples DNA methylation to transcriptional repression, has been implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell cycle progression and development. It has also been proven that MBD1 is involved in tumor development and progression. However, whether MBD1 is involved in tumorigenesis, especially in gallbladder cancer, is totally unknown. Human GBC-SD and SGC996 cells were used to perform experiments. Invasion, wound healing and colony formation assays were performed to evaluate cell viability. A CCK-8 assay was performed to assess gallbladder cancer cell viability after gemcitabine treatment. Western blot analysis was used to evaluate changes in protein expression. Human gallbladder cancer tissues and adjacent nontumor tissues were subjected to immunohistochemical staining to detect protein expression. We found that MBD1 expression was significantly upregulated in gallbladder cancer tissues compared with that in surrounding normal tissues according to immunohistochemical analysis of 84 surgically resected gallbladder cancer specimens. These data also indicated that higher MBD1 expression was correlated with lymph node metastasis and poor survival in gallbladder cancer patients. Overexpression and deletion in vitro validated MBD1 as a potent oncogene promoting malignant behaviors in gallbladder cancer cells, including invasion, proliferation and migration, as well as epithelial-mesenchymal transition. Studies have demonstrated that epithelial-mesenchymal transition is common in gallbladder cancer, and it is well known that drug resistance and epithelial-mesenchymal transition are very closely correlated. Herein, our data show that targeting MBD1 restored gallbladder cancer cell sensitivity to gemcitabine chemotherapy. Taken together, the results of our study revealed a novel function of MBD1 in gallbladder cancer tumor development and progression through participation in the gallbladder cancer epithelial-mesenchymal transition program, which is involved in resistance to gemcitabine chemotherapy. Thus, MBD1 may be a potential therapeutic target for gallbladder cancer. | Authentic |
Text : Pleural effusion (PE) can be divided into benign pleural effusion (BPE) and malignant pleural effusion (MPE). There is no consensus on the identification of lung cancer-associated MPE using the optimal cut-off levels from five common tumor biomarkers (CEA, CYFRA 21-1, CA125, SCC-Ag, and NSE). Therefore, we aimed to find indicators for the auxiliary diagnosis of lung cancer-associated MPE by analyzing and then validating the optimal threshold levels of these biomarkers in pleural fluid (PF) and serum, as well as the PF/serum ratio. The study has two sets of patients, i.e. the training set and the test set. In the training set, 348 patients with PE, between January 1, 2016 and December 31, 2017, were divided into BPE and MPE based on the cytological diagnosis. Subsequently, the optimal cut-off levels of tumor biomarkers were analyzed. In the test set, the diagnostic compliance rate was verified with 271 patients with PE from January 1, 2018 to July 31, 2019 to evaluate the auxiliary diagnostic value of the aforementioned indicators. In the training set, PF CEA at the cut-off value of 5.23 ng/ml was the most effective indicator for MPE compared with other tumor biomarkers (all p < 0.001). In the test set, PF CEA at the cut-off value of 5.23 ng/ml showed the highest sensitivity, specificity and accuracy, positive and negative predictive value among other tumor biomarkers, which were 99.0%, 69.1%, 91.6%, 90.7%, and 95.9%, respectively. PF CEA at the cut-off level of 5.23 ng/ml was the most effective indicator for identifying lung cancer-associated MPE among the five common tumor biomarkers. | Authentic |
Text : We tried to elaborate the molecular mechanism of ETS-like transcription factor 4 (ELK4) affecting gastric cancer (GC) progression through M2 polarization of macrophages mediated by lysine-specific demethylase 5A (KDM5A)-Praja2 (PJA2)-kinase suppressor of ras 1 (KSR1) axis. GC expression dataset was obtained from GEO database, and the downstream regulatory mechanism of ELK4 was predicted. Tumor-associated macrophages (TAMs) were isolated from GC tissues. The interaction among ELK4, KDM5A, PJA2 and KSR1 was analyzed by dual luciferase reporter gene, ChIP and Co-IP assays. The stability of KSR1 protein was detected by cycloheximide (CHX) treatment. After TAMs were co-cultured with HGC-27 cells, HGC-27 cell biological processes were assessed through gain- and loss-of function assays. Tumorigenicity was detected by tumorigenicity test in nude mice. In GC and TAMs, ELK4, KDM5A and KSR1 were highly expressed, while PJA2 was lowly expressed. M2 polarization of macrophages promoted the development of GC. ELK4 activated KDM5A by transcription and promoted macrophage M2 polarization. KDM5A inhibited the expression of PJA2 by removing H3K4me3 of PJA2 promoter, which promoted M2 polarization of macrophages. PJA2 reduced KSR1 by ubiquitination. ELK4 promoted the proliferative, migrative and invasive potentials of GC cells as well as the growth of GC xenografts by regulating KSR1. ELK4 may reduce the PJA2-dependent inhibition of KSR1 by transcriptional activation of KDM5A to promote M2 polarization of macrophages, thus promoting the development of GC. | Counterfeit |
Text : Resistance towards imatinib (IM) remains troublesome in treating many chronic myeloid leukemia (CML) patients. Heme oxygenase-1 (HO-1) is a key enzyme of antioxidative metabolism in association with cell resistance to apoptosis. Our previous studies have shown that overexpression of HO-1 resulted in resistance development to IM in CML cells, while the mechanism remains unclear. In the current study, the IM-resistant CML cells K562R indicated upregulation of some of the histone deacetylases (HDACs) compared with K562 cells. Therefore, we herein postulated HO-1 was associated with HDACs. Silencing HO-1 expression in K562R cells inhibited the expression of some HDACs, and the sensitivity to IM was increased. K562 cells transfected with HO-1 resisted IM and underwent obvious some HDACs. These findings related to the inhibitory effects of high HO-1 expression on the reactive oxygen species (ROS) signaling pathway that negatively regulated HDACs. Increased expression of HO-1 activated HDACs by inhibiting ROS production. In summary, HO-1, which is involved in the development of drug resistance in CML cells by regulating the expression of HDACs, is probably a novel target for improving CML therapy. | Authentic |
Text : To examine the expression level of microRNA-485-5p (miRNA-485-5p) in acute myeloid leukemia (AML) and its biological function in regulating the proliferative ability of AML through targeting SALL4. Serum level of miRNA-485-5p in AML patients and healthy controls was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). MiRNA-485-5p level in AML cell lines was detected by qRT-PCR as well. Proliferative and apoptotic changes in AML5 and U937 cells overexpressing miRNA-485-5p were assessed. Subsequently, the regulatory effect of miRNA-485-5p on SALL4 level was evaluated. Rescue experiments were conducted to uncover the role of miRNA-485-5p/SALL4 regulatory loop in regulating cellular behaviors of AML. Compared with healthy controls, serum level of miRNA-485-5p was lower in AML patients. MiRNA-485-5p was similarly downregulated in AML cell lines. Overexpression of miRNA-485-5p stimulated proliferation and alleviated apoptosis in AML. SALL4 level was downregulated by transfection of miRNA-485-5p mimics in AML5 and U937 cells. Overexpression of SALL4 could reverse the regulatory effect of miRNA-485-5p on proliferative and apoptotic abilities of AML. MiRNA-485-5p is downregulated in AML. Overexpression of miRNA-485-5p alleviates the malignant progression of AML through downregulating SALL4. | Authentic |
Text : Cervical cancer (CC) is the 4th most common cancer-related death in gynecological cancer worldwide. It has been reported that many lncRNAs contribute to oncogenesis although the fundamental mechanisms are basically unknown. Here, we aimed to identify a novel lncRNA H1FX-AS1 and explore a ceRNA network in CC oncogenesis and progression. The expression level and the association with the prognosis of H1FX-AS1 in CC patients were analyzed based on Cancer Genome Atlas (TCGA) datasets, and further verified in 50 CC patients. The biological role of H1FX-AS1 was investigated in vitro and in vivo by over-expression of H1FX-AS1 in CC cells; the potential binding sites between H1FX-AS1 and miRNA, between miR-324-3p and DACT1 were predicted by LncBASE and Targetscan respectively, which were further verified by dual-luciferase reporter assay, RNA pull-down and point mutation; the relationship between genes was analyzed by Pearson correlation; the rescue experiments were used to further explore the involved molecular mechanism. Lower H1FX-AS1 expression in CC tissues was found to be associated with the poor prognosis of CC patients. Over-expression of H1FX-AS1 inhibited CC cell proliferation, migration and invasion, while induced apoptosis by sponging miR-324-3p to up-regulate the DACT1 expression level. A novel lncRNA H1FX-AS1 was identified, which acted as a competing endogenous RNA (ceRNA) of miR-324-3p to inhibit DACT1 mediated CC progression. Therefore, H1FX-AS1 is a new prognostic predictor and targeting the factors in the H1FX-AS1/miR-324-3p/DACT1 axis is the novel potential therapeutic strategy for CC. | Authentic |
Text : Ets related gene (ERG) is a transcription factor that is overexpressed in 40% of prostate tumors due to a gene fusion between ERG and TMPRSS2. Because ERG functions as a driver of prostate carcinogenesis, understanding the mechanisms that influence its turnover may provide new molecular handles to target the protein. Previously, we found that ERG undergoes ubiquitination and then is deubiquitinated by USP9X in prostate cancer cells to prevent its proteasomal degradation. Here, we identify Tripartite motif-containing protein 25 (TRIM25) as the E3 ubiquitin ligase that ubiquitinates the protein prior to its degradation. TRIM25 binds full-length ERG, and it also binds the N-terminally truncated variants of ERG that are expressed in tumors with TMPRSS2-ERG fusions. We demonstrate that TRIM25 polyubiquitinates ERG in vitro and that inactivation of TRIM25 resulted in reduced polyubiquitination and stabilization of ERG. TRIM25 mRNA and protein expression was increased in ERG rearrangement-positive prostate cancer specimens, and we provide evidence that ERG upregulates TRIM25 expression. Thus, overexpression of ERG in prostate cancer may cause an increase in TRIM25 activity, which is mitigated by the expression of the deubiquitinase USP9X, which is required to stabilize ERG. | Authentic |
Text : Vesicular stomatitis virus (VSV) has shown promise in cancer treatment. However, it achieved limited effects against lung cancer. Lung cancer has intrinsic mechanisms that render resistance to VSV. In this study, we attempted to explore the expression of the anti-apoptotic factor Livin in lung adenocarcinoma and its possible relationship to VSV vulnerability. We found VSV induced apoptosis in a time- and dose-dependent manner, with the concomitant change in the expression of Livin. We elevated the expression of Livin both transiently and stably, and the cells became insensitive to VSV treatment. We further found the BIR domain of Livin was mainly responsible for its modulation effects. This finding suggested a possible interaction with the second mitochondria-derived activator of caspase (SMAC). The knock-down of SMAC also inhibited apoptosis by VSV. The relationship was confirmed by the co-immunoprecipitation. Finally, we knocked down the endogenous Livin, and the knock-down sensitized cells to VSV treatment. Our results suggested the important role of Livin and its partner molecule in the process of VSV treatment. | Authentic |
Text : Cervical cancer is the most common malignancy of the female reproductive tract, and the poor response to prophylactic vaccines and the toxicity of high‑dose chemotherapeutic drugs have limited their clinical application. Spermidine, a natural polyamine detected in all eukaryotic organisms, exhibits functions that promote longevity in multiple model systems and may constitute a promising agent for cancer treatment. However, the potential effectiveness of spermidine in cervical cancer has not yet been fully elucidated, and the underlying molecular mechanisms remain unclear. In the present study, we aimed to assess the effects of spermidine on proliferation and apoptosis of HeLa cells (a cervical cancer cell line). Firstly, CCK‑8 and flow cytometric assays revealed that spermidine reduced the proliferation of HeLa cells in a dose‑dependent fashion by arresting the cell cycle at the S phase. Secondly, flow cytometry incorporating Annexin V‑FITC/PI‑staining revealed that spermidine promoted the apoptosis of HeLa cells, and western blot analysis revealed that spermidine activated autophagy. Finally, spermidine‑activated autophagy mediated the inhibition of cell proliferation by spermidine and spermidine‑induced apoptosis in HeLa cells. Collectively, these results revealed a novel function for spermidine in inhibiting cellular proliferation and inducing apoptosis of HeLa cells by activating autophagy, which may have important implications for the use of spermidine in cervical cancer therapy. | Authentic |
Text : Colorectal cancer (CRC) is one of the leading causes of cancer-related death, with most of the people who have the disease developing numerous liver metastases. Sixty percent of colon cancer patients have liver metastases. Only 25% of those with resectable hepatic metastases are alive, and recurrence occurs in nearly half of these cases. Regardless of the fact that left-sided cancer has a higher rate of liver metastases, past study reveals that left- and right-sided liver metastatic colon cancer patients have different survival rates. Hepatic artery infusion (HAI) combined with systemic chemotherapy is a treatment option for patients with unresectable liver-only or liver-dominant colon liver metastases. Although HAI has only been performed in a few locations previously, this study used randomized trials of floxuridine (FUDR) to characterize patient selection and first perioperative results during the deployment of a new HAI program. In this research, we also looked at the technical aspects of placing implantable pumps and catheters for HAI chemotherapy, as well as the efficacy, morbidity, and outcomes of this therapy in colon cancer patients with numerous liver metastases. The parameters like toxicity, overall survival rate, response rate, and progression-free response for the suggested therapy are also analyzed. These findings have important implications for colon cancer adjuvant HAI chemotherapy. | Counterfeit |
Text : Deregulation of protein translation control is a hallmark of cancers. Eukaryotic initiation factor 4A2 (EIF4A2) is required for mRNA binding to ribosome and plays an important role in translation initiation. However, little is known about its functions in colorectal cancer (CRC). Analysis of CRC transcriptome data from TCGA identified that EIF4A2 was associated with poor prognosis. Immunohistochemistry study of EIF4A2 was carried out in 297 paired colorectal tumor and adjacent normal tissue samples. In vitro and in vivo cell-biological assays were performed to study the biological functions of EIF4A2 on experimental metastasis and sensitivity to oxaliplatin treatment. Bioinformatic prediction, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay were carried out to unveil the transcription factor of EIF4A2 regulation. EIF4A2 Expression is significantly higher in colorectal tumors. Multivariate analysis suggests EIF4A2 as an independent predictor of overall, disease-free and progression-free survival. Dysfunction of EIF4A2 by genetic knock-down or small-molecule inhibitor silvestrol dramatically inhibited CRC invasion and migration, sphere formation and enhanced sensitivity to oxaliplatin treatment in vitro and in vivo. Notably, EIF4A2 knock-down also suppressed lung metastasis in vivo. qRT-PCR and immunoblotting analyses identified c-Myc as a downstream target and effector of EIF4A2. ChIP and dual-luciferase reporter assays validated the bioinformatical prediction of ZNF143 as a specific transcription factor of EIF4A2. EIF4A2 promotes experimental metastasis and oxaliplatin resistance in CRC. Silvestrol inhibits tumor growth and has synergistic effects with oxaliplatin to induce apoptosis in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models. | Authentic |
Text : Sentinel lymph node biopsy (SLNB) can be performed when node-positive disease is converted to node-negative status after neoadjuvant chemotherapy (NCT). Tattooing nodes might improve accuracy but supportive data are limited. This study aimed to investigate the feasibility of charcoal tattooing metastatic axillary lymph node (ALN) at presentation followed by SLNB after NCT in breast cancers. Twenty patientswith cytology-proven node metastases prospectively underwent charcoal tattooing at diagnosis. SLNB using dual tracers and axillary surgery after NCT were then performed. The detection rate of tattooed node and diagnostic performance of SLNB were analyzed. All patients underwent charcoal tattooingwithout significant morbidity. Sentinel and tattooed nodes could be detected during surgery after NCT. Nodal pathologic complete response was achieved in 10 patients. Overall sensitivity, false-negative rate (FNR), negative predictive value, and accuracy of hot/blue SLNB were 80.0%, 20.0%, 83.3%, and 90.0%, respectively. Retrieving more nodes and favorable nodal response were associated with improved performance. The best accuracy was observed when excised tattooed node was calculated together (FNR, 0.0%). Cold/non-blue tattooed nodes of five patients were removed during non-sentinel axillary surgery but clinicopathological parameters did not differ compared to patients with hot/blue tattooed node detected during SLNB, suggesting the importance of the tattooing procedure itself to improve performance. Charcoal tattooing of cytology-confirmed metastatic ALN at presentation is technically feasible and does not limit SLNB after NCT. The tattooing procedure without additional preoperative localization is advantageous for improving the diagnostic performance of SLNB in this setting. | Authentic |
Text : Preeclampsia (PE) is a hypertensive disease associated with vascular oxidative stress (OS). Besides, cell response to OS triggers growth arrest and DNA damage inducible alpha (Gadd45a). Herein, we investigated the effect of Gadd45a on OS in PE. Umbilical cord tissues and peripheral blood samples were collected from PE patients and normal pregnant women. Immunohistochemistry was applied to identify Gadd45a level and extent of p38 phosphorylation. To verify the effect of Gadd45a on CRL1730 human umbilical vein endothelial cell (HUVEC) behavior, HUVECs were treated with hypoxia/reoxygenation (H/R) and Gadd45a-siRNA or P79350. OS products were detected using thiobarbituric acid-reactive-substance assay, immune enzyme assay, enzyme-linked immunosorbent assay (ELISA) and super oxide dismutase (SOD) kit. HUVEC behaviors were evaluated using flow cytometry, wound-healing test, and Transwell assay. The tube formation ability was assessed using in vitro tube formation assay. PE umbilical cord tissues exhibited increased Gadd45a expression, extent of p38 phosphorylation, 8-isoprostane and oxidatively modified low density lipoprotein (Ox-LDL) and decreased SOD levels. HUVECs treated with H/R or agonist + H/R showed similar expression tendencies of related genes, enhanced apoptosis and inhibited migration, invasion, and blood vessel formation. Gadd45a-siRNA conferred alleviation to OS with decreased apoptosis, greater cell migration, invasion and blood vessel, which appeared to be weakened by treatment of Gadd45a siRNA + P79350. Over-expression of Gadd45a and activation of the p38 MAPK signaling pathway are associated with OS in PE. Furthermore, Gadd45a knockdown promotes cell migration and invasion, and the tube formation, thus alleviating OS in PE. | Counterfeit |
Text : Acquisition of features of mesenchymal cells represents a key step of metastatic progression of cancer cells and searching for mechanisms underlying the acquisition will help design novel clinical strategies for suppressing the metastatic progression. The Deleted in Liver Cancer-1 (DLC-1) gene is a p122/RhoGAP tumor/metastatic suppressor gene. However, the mechanism underlying DLC-1's inhibition of metastasis still remains largely unknown. In this study, we revealed that the DLC-1-deficient, but not the DLC-1-competent, human non-small cell lung carcinoma cells (NSCLCs) could acquire the TGF-β1-induced expression of CD105, a common surface marker of mesenchymal stem cells, with consequent increase in CD105-associated cell motility. Interestingly, the induced CD105 expression and cell motility were subjected to the inhibition by the DLC-1-RhoA-Rock1 signaling through inhibiting the serine phosphorylation at a linker region, but not at the C-terminus, of the Smad3 protein and Smad3 protein nuclear translocation down the canonical TGF-β1 signaling. In addition, the evidence suggested that DLC-1 very likely exerted its inhibitory effects on the TGF-β1 signaling and the associated CD105 acquisition in both the cytoplasm and the nucleus. Consistent to the in vitro findings, a reverse correlation between CD105 and DLC-1 in protein expression was identified in primary NSCLC tissues and their surrounding non-tumor tissues. In summary, this study revealed a novel anti-metastasis mechanism governed by the DLC-1 tumor/metastasis suppressor, thus helping design new diagnostic and therapeutic approaches for NSCLCs. | Authentic |
Text : Circulating tumour DNA (ctDNA) is a noninvasive method of detecting tumours, and its prognostic significance in hepatocellular carcinoma (HCC) patients is controversial. We conducted a systematic review of published research data to evaluate the prognostic value of ctDNA in HCC patients. The PubMed, Embase, Web of Science, Cochrane Library, and Scopus databases were searched to identify eligible studies reporting disease-free survival (DFS) and overall survival (OS) stratified by ctDNA prior to January 2022. We evaluated the quality and design of these studies. The hazard ratio (HR) was used to combine the survivorship curve and univariate and multivariate results of the included studies. In total, 8 articles were included, encompassing 577 HCC patients. The results of survival curve analysis showed that ctDNA was related to poor OS and DFS, and the effect sizes were HR = 2.44, 95% CI (1.42, 4.20), P=0.001; HR = 2.63, 95% CI (1.96, 3.53), P < 0.001. The univariate analysis results showed that ctDNA was related to poor OS (HR = 4.48, 95% CI (1.17, 13.70), P=0.003). The combined results of multivariate analysis showed that ctDNA was related to a shorter risk of OS (HR = 3.74, 95% CI (1.45, 9.65), P=0.006). The univariate and multivariate descriptive analysis results showed that ctDNA was related to shorter DFS, and the effect sizes were HR = 3.28, 95% CI (1.23, 11.30), P=0.011; HR = 3.01, 95% CI (1.11, 10.5), P < 0.001. The evidence provided by this analysis suggests that ctDNA may be a prognostic biomarker and is negatively correlated with the survival of HCC patients. Mutations in the TERT and SOCS3 promoters in ctDNA are associated with poor prognosis and are expected to become good targets for liquid biopsy and to help select treatment strategies. | Authentic |
Text : Hypopharyngeal cancer is a distinct type of malignant head and neck tumor, which exhibits low sensitivity to anti-cancer drugs. The importance of developing methods for reducing chemotherapy resistance, and improving and enhancing prognosis has previously been emphasized and is considered a challenge for effective clinical treatment of hypopharyngeal cancer. The current study investigated the effects of co‑expression of inhibitor of growth protein 4 (ING4) and P53, a tumor suppressor gene, on chemosensitivity to cisplatin in human hypopharyngeal cancer xenografts in vivo, and the potential molecular mechanisms involved. A tumor model was established by injecting athymic nude mice with FADU human hypopharyngeal cancer cells. Five days after intratumoral and peritumoral injections of an empty adenoviral vector (Ad), Ad‑ING4‑P53, cisplatin, or a combination of Ad‑ING4‑P53 and cisplatin (Ad‑ING4‑P53 + cisplatin) every other day for 5 days, the mice were euthanized and their tumors, livers, and kidneys were removed. The tumor weights were used to calculate the inhibition rate, and the expression levels of ING4 and P53 were detected by reverse transcription‑polymerase chain reaction. Additionally, apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunohistochemistry determined the levels ING4, P53, B‑cell lymphoma‑2 (Bcl‑2) and Bcl‑2 associated X protein (Bax) protein expression. The results demonstrated increased expression of ING4 and P53 in the Ad‑ING4‑P53 groups compared with PBS and Ad groups, indicating successful introduction of the genes into the tumor cells. Notably, the Ad‑ING4‑P53 + cisplatin group exhibited a higher inhibition rate compared with the four other groups. The results of immunohistochemistry analysis demonstrated that Bax expression was increased and Bcl‑2 was decreased in the Ad‑ING4‑P53 + cisplatin group. This suggested that the enhanced cisplatin chemosensitivity with Ad-ING4-P53 gene therapy in hypopharyngeal cancer xenografts may be associated with apoptosis induction through upregulation of Bax expression and downregulation of Bcl‑2. The results of the present study indicated that gene therapy combined with cisplatin treatment may be a promising treatment for human hypopharyngeal cancer. | Authentic |
Text : Kidney renal clear cell carcinoma (KIRCC) is a highly heterogeneous and lethal cancer that can arise in patients with renal disease. DeepSurv combines a deep feed-forward neural network with a Cox proportional hazards function and could provide optimized survival results compared with convenient survival analysis. This study used an improved DeepSurv algorithm to identify the candidate genes to be targeted for treatment on the basis of the overall mortality status of KIRCC subjects. All the somatic mutation missense variants of KIRCC subjects were abstracted from TCGA-KIRC database. The improved DeepSurv model (95.1%) achieved greater balanced accuracy compared with the DeepSurv model (75%), and identified 610 high-risk variants associated with overall mortality. The results of gene differential expression analysis also indicated nine KIRCC mortality-risk-related pathways, namely the tRNA charging pathway, the D-myo-inositol-5-phosphate metabolism pathway, the DNA double-strand break repair by nonhomologous end-joining pathway, the superpathway of inositol phosphate compounds, the 3-phosphoinositide degradation pathway, the production of nitric oxide and reactive oxygen species in macrophages pathway, the synaptic long-term depression pathway, the sperm motility pathway, and the role of JAK2 in hormone-like cytokine signaling pathway. The biological findings in this study indicate the KIRCC mortality-risk-related pathways were more likely to be associated with cancer cell growth, cancer cell differentiation, and immune response inhibition. The results proved that the improved DeepSurv model effectively classified mortality-related high-risk variants and identified the candidate genes. In the context of KIRCC overall mortality, the proposed model effectively recognized mortality-related high-risk variants for KIRCC. | Authentic |
Text : Colon cancer, also known as colorectal carcinoma (CRC), remains to be one of the most mainsprings of cancer-produced deaths entire world. We planned to grab the role and possible biological cause of a long noncoding RNA, namely, small nucleolar RNA host gene 15 (SNHG15), in CRC. The mRNA level of SNHG15 in CRC tissues and cells was detected, followed by investigating the impacts of the depression of SNHG15 on CRC cell proliferation (viability and colony-forming), apoptosis, migration, and invasion. Moreover, the association between SNHG15 and miR-141 and the correlation between miR-141 and SIRT1 were also explored. Besides, the influences of dysregulated SNHG15 on the Wnt/β-catenin signal-related proteins were determined. SNHG15 was highly expressed in CRC tissues and cells. Depression of SNHG15 depressed proliferation, enhanced apoptosis, and repressed the migration and invasion of CRC cells. In addition, SNHG15 presented a downside tendency on regulating miR-141, and the miR-141 inhibitor dramatically changeover the impacts of SNHG15 depression on tumor growth and metastasis. Moreover, SIRT1 was verified as a functional target of miR-141 in CRC cells. Besides, the suppression of SNHG15 remarkably controlled activating the Wnt/β-catenin signals, which was reversed after inhibiting miR-141 at the same time. The investigated results in this research revealed that the increased expression of SNHG15 may enhance the process of CRC by acting as a ceRNA in regulating SIRT1 expression by sponging miR-141. Thus we propose that Wnt/β-catenin signals may be a downriver regulator in mediating the impacts of SNHG15 in CRC and SNHG15-miR-141-SIRT1 axis may pave a new sight in explaining the biological processes of CRC. | Counterfeit |