syedzayyan/paper_mill_benchmark huggingface dataset:
Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression

Background emerging evidence supports the pivotal roles of adipocytes in breast cancer progression.Tumour induced beige/brown adipose tissue differentiation contributes to the hypermetabolic state of the breast cancer.However, the mediators and mechanisms remain unclear.Methods survival probabilities were estimated using the kaplan–meier method based on immunohistochemistry results.Biochemical studies were performed to characterize the novel interrelation between breast cancer cells and adipocytes.Results we show that tumour-surrounding adipocytes exhibit an altered phenotype in terms of upregulated beige/brown characteristics and increased catabolism associated with an activated state characterized by the release of metabolites, including free fatty acids, pyruvate, lactate and ketone bodies.Likewise, tumour cells cocultivated with mature adipocytes exhibit metabolic adaptation and an aggressive phenotype in vitro and in vivo.Mechanistically, we show that tumour cells induce beige/brown differentiation and remodel metabolism in resident adipocytes by exosomes from the co-culture system that carry high levels of mi rna-144 and mi rna-126.Mi rna-144 promotes beige/brown adipocyte characteristics by downregulating the map3k8/erk1/2/pparγ axis, and exosomal mi rna-126 remodels metabolism by disrupting irs/glut-4 signalling, activating the ampk/autophagy pathway and stabilizing hif1α expression in imminent adipocytes.In vivo inhibition of mi rna-144 or mi rna-126 decreases adipocyte–induced tumour growth.Conclusions these results demonstrate that by inducing beige/brown differentiation and enhancing catabolism in recipient adipocytes, exosomal mi rna-144 and mi rna-126 from the tumour-adipocyte interaction reprogram systemic energy metabolism to facilitate tumour progression.

Journal: Journal of Experimental & Clinical Cancer Research: (CR) (2019)
Publication types: Research Article;
SP1-induced lncRNA AGAP2-AS1 expression promotes chemoresistance of breast cancer by epigenetic regulation of MyD88

Background resistance to trastuzumab has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome.Cell behavior can be modulated by long non-coding rnas (lnc rnas), but the contribution of lnc rnas in trastuzumab resistance to breast cancer is largely unknown.To this end, the involvement and regulatory function of lnc rna agap2-as1 in human breast cancer are yet to be investigated.Methods trastuzumab-resistant skbr-3 and bt474 cells were obtained by continuous culture with 5 mg/m l trastuzumab for 6 months.Rt-q pcr assay was used to determine the expression of agap2-as1 in tissues and cells.Rna fluorescence in situ hybridization was used to investigate the subcellular location of agap2-as1 in breast cancer cells.Bioinformatic analysis, chromatin immunoprecipitation (ch ip), rna immunoprecipitation (rip), western blotting, and immunofluorescence were carried out to verify the regulatory interaction of agap2-as1, creb-binding protein (cbp), and my d88.In addition, a series of in vitro assays and a xenograft tumor model were used to analyze the functions of agap2-as1 in breast cancer cells.Results agap2-as1 was upregulated and transcriptionally induced by sp1 in breast cancer.Overexpression of agap2-as1 promoted cell growth, suppressed apoptosis, and caused trastuzumab resistance, whereas knockdown of agap2-as1 showed an opposite effect.My d88 was identified as a downstream target of agap2-as1 and mediated the agap2-as1-induced oncogenic effects.Mechanistically, the rip assay revealed that agap2-as1 could bind to cbp, a transcriptional co-activator.Ch ip assays showed that agap2-as1-bound cbp increased the enrichment of h3k27ac at the promoter region of my d88, thus resulting in the upregulation of my d88.Gain- and loss-of-function assays confirmed that the nf-κb pathway was activated by my d88 and agap2-as1.Furthermore, high agap2-as1 expression was associated with poor clinical response to trastuzumab therapy in breast cancer patients.Conclusion agap2-as1 could promote breast cancer growth and trastuzumab resistance by activating the nf-κb signaling pathway and upregulating my d88 expression.Therefore, agap2-as1 may serve as a novel biomarker for prognosis and act as a therapeutic target for the trastuzumab treatment.

Journal: Journal of Experimental & Clinical Cancer Research: (CR) (2018)
Publication types: Research Article;
MicroRNA-208a-3p functions as an oncogene in colorectal cancer by targeting PDCD4

Accumulating evidences have shown micro rnas (mi rnas) play important roles in the progression of human cancers including colorectal cancer (crc).However, the biological function and molecular mechanism of mi rnas in crc still remains to be further investigated.Using microarray, we found and confirmed that mi r-208a-3p was up-regulated in crc tissues.Its high expression was statistically associated with distant metastasis and tnm stage.Functional assays revealed inhibition of mi r-208a-3p suppressed proliferation, invasion and migration, and induced cell apoptosis of crc cells.Moreover, we identified programmed cell death protein 4 (pdcd4), a well-known tumor suppressor, is a direct target of mi r-208a-3p.We also found that overexpression of pdcd4 suppressed cell proliferation, invasion, and migration.Importantly, silencing of pdcd4 efficiently abrogated the promoting effects on crc cells proliferation, invasion, and migration caused by inhibition of mi r-208a-3p.Our findings confirmed the oncogenic role of mi r-208a-3p via targeting pdcd4 in crc, identifying mi r-208a-3p as a potential diagnosis and therapeutic biomarker for crc.

Journal: Bioscience Reports (2019)
Publication types: Research Article;
Upregulated circular RNA VANGL1 contributes to progression of non-small cell lung cancer through inhibition of miR-195 and activation of Bcl-2

Circular rnas (circ rnas), a group of non-coding rnas, play an important role in cancer biology, and in the present study, we aimed to clarify the expression profiles and biological functions of circ rna circ vangl1 in non-small cell lung cancer (nsclc).The results showed that circ vangl1 was overexpressed in human nsclc tissues and cell lines.Circ vangl1 expression was closely associated with tumor size, tnm stage and overall survival of nsclc patients.Further loss-of-function analysis revealed that knockdown of circ vangl1 inhibited proliferation and induced apoptosis in nsclc cell lines.The migration and invasion of nsclc cells were also suppressed by circ vangl1 knockdown.In addition, we predicted that circ vangl1 might serve as a competing endogenous rna (ce rna), becoming a sink for mi r-195, thereby modulating the expression of bcl-2 in nsclc cells.Rescue experiments demonstrated that mi r-195 inhibitor abrogated the beneficial role of circ vangl1 knockdown in nsclc cells.Taken together, we conclude that circ vangl1 functions as an oncogene to promote nsclc progression partly through mi r-195/bcl-2 axis, which might be a novel therapeutic target for nsclc patients.

Journal: Bioscience Reports (2019)
Publication types: Research Article;
MicroRNA-302c enhances the chemosensitivity of human glioma cells to temozolomide by suppressing P-gp expression

Increasing evidence indicates that micro rnas (mi rnas) participate in the regulation of chemoresistance in a variety of cancers including glioma.However, the molecular mechanism underlying the development of chemoresistance in glioma is not well understood.The aim of the present study was to explore the role of mi rnas in the chemosensitivity of glioma cells and the underlying mechanism.By microarray and q rt-pcr, we observed significant down-regulation of micro rna-302c (mi r-302c) in the temozolomide (tmz)-resistant human glioma tissues/cells.The low expression of mi r-302c was closely associated with poor prognosis and chemotherapy resistant in patients.Mi r-302c up-regulation re-sensitized u251mg-tmz cells and ln229-tmz cells to tmz treatment, as evidenced by inhibition of the cell viability, cell migration, and invasion capacity, and promotion of the apoptosis after tmz treatment.Furthermore, p-glycoprotein (p-gp) was identified as a functional target of mi r-302c and this was validated using a luciferase reporter assay.In addition, p-gp was found to be highly expressed in u251mg-tmz cells and there was an inverse correlation between p-gp and mi r-302c expression levels in clinical glioma specimens.Most importantly, we further confirmed that overexpression of p-gp reversed the enhanced tmz-sensitivity induced by mi r-302c overexpression in u251mg-tmz and ln229-tmz cells.Our finding showed that up-regulation of mi r-302c enhanced tmz-sensitivity by targeting p-gp in tmz-resistant human glioma cells, which suggests that mi r-302c would be potential therapeutic targets for chemotherapy-resistant glioma patients.

Journal: Bioscience Reports (2019)
Publication types: Research Article;
Effects of FOSL1 silencing on osteosarcoma cell proliferation, invasion and migration through the ERK/AP-1 signaling pathway

Osteosarcoma (os), as the most frequent primary malignancy of bone, is characterized by the presence of malignant mesenchymal cells.In the current study, our aim was to explore the possible effects fos‐like antigen‐1 (fosl1) had on the silencing regarding os cell proliferation, invasion, and migration through the activation of the extracellular‐signal‐regulated kinase (erk)/activator protein‐1 (ap‐1) signaling pathway.After the collection of os on top of already having the adjacent normal tissue samples, the protein positive expression rate of fosl1 was then measured by implementing the use of immunohistochemistry and discovered that fosl1 was robustly expressed in os.Later, to better grasp the impact fosl1 projects on os and its underlying mechanism, we determined the os related genes as well as the erk/ap‐1 signaling pathway related genes expression by using a reverse‐transcription quantitative polymerase chain reaction and western blot assay techniques.The results of the aforementioned two experiments revealed that the fosl1 depletion had downregulated the expression of os related genes by simultaneously downregulating the erk/ap‐1 signaling pathway.Moreover, cell proliferation, cycle, apoptosis, invasion, and migration of fos1 were all tested by using a cell counting kit‐8 assay, flow cytometry, transwell assay, and scratch test, and these results presented that silencing of the fosl1 gene inhibited os cell proliferation, invasion, and migration.Our findings revealed a novel mechanism by which fosl1 depletion played a significantly negative role in the os progression through the regulation of the erk/ap‐1 signaling pathway.Functional suppression of fosl1 might be a future therapeutic strategy regarding os.

Journal: Journal of Cellular Physiology (2018)
Publication types: Research Article;
17β-estradiol binding to ERα promotes the progression of prolactinoma through estrogen-response element-induced CaBP-9k upregulation

17β-estradiol (e2) is considered to be an important instigator of prolactinoma, and can positively regulate the expression of calbindin-d9k (ca bp-9k) which contains an estrogen responsive element (ere) via estrogen receptors (ers).However, the detailed mechanism of e2 in promoting ca bp-9k expression and their roles in prolactinoma progression remain unclear.Here, we aimed to characterize it.The luciferase gene reporter assay with luc-ere transfection showed that e2 treatment significantly enhanced the transcriptional level of ca bp-9k, whereas ca bp-9k activity was reduced when gh3 and mmq cells were treated with azd9496, an antagonist of erα.E2 treatment increased the protein expressions of ca bp-9k and erα but not erβ, whereas this effect was also abolished when cells were treated with azd9496.Besides, immunoprecipitation (ip) and immunofluorescence assays demonstrated that ca bp-9k could directly interact with erα not erβ, and chromatin ip (ch ip) assay showed that erα could bind to ere of the ca bp-9k promoter.Moreover, cell counting kit-8 (cck-8) and flow cytometry assays showed that e2 treatment significantly enhanced cell viability and inhibited cell apoptosis, but these effects were all abolished when erα was down-regulated by short hairpin rna (sh rna) or inhibited by azd9496, as well as ca bp-9k suppression in both gh3 and mmq cell lines.Taken together, these findings indicated that e2 stimulation promoted prolactin cell proliferation and inhibited cell apoptosis through erα-induced ca bp-9k up-regulation, which then accelerated the advanced progression of prolactinoma.

Journal: Bioscience Reports (2020)
Publication types: Research Article;
Human Umbilical Cord Mesenchymal Stem Cells-Derived Exosomal MicroRNA-18b-3p Inhibits the Occurrence of Preeclampsia by Targeting LEP

Exosomes derived from human umbilical cord mesenchymal stem cells (huc mscs) expressing micro rnas have been highlighted in human diseases.However, the detailed molecular mechanism of huc mscs-derived exosomal mi r-18b-3p on preeclampsia (pe) remains further investigation.We aimed to investigate the effect of exosomes and mi r-18b-3p/leptin (lep) on occurrence of pe.The morphology of the huc msc and huc msc-exosomes (exos) was identified.The exosomes were infected with different lentivirus expressing mi r-18b-3p to explore the role of mi r-18b-3p in pe.The pe rat model was established by intraperitoneal injection of n -nitro- l -arginine methyl ester.The expression of lep and mi r-18b-3p was tested in pe rat placenta tissues.Also, the effect of exosomes on lep and mi r-18b-3p expression was detected.The systolic blood pressure (sbp), proteinuria, inflammatory factors, the weight of fetal rat and placenta and cell apoptosis in pe rats were detected.Finally, the relationship between mi r-18b-3p and lep was verified using dual-luciferase reporter gene assay and rna pull-down assay.Exosomes, restoring mi r-18b-3p or inhibiting lep reduced sbp and proteinuria of pe rats as well as increased the weight of fetal rat and placenta, decreased serum levels of inflammatory factors as well as suppressed apoptotic cells of pe rats, exerting a suppressive effect on pe progression.Mi r-18b-3p was decreased and lep was increased in placenta tissues of pe rats.Lep was the direct target gene of mi r-18b-3p.Upregulation of mi r-18b-3p or treatment of the exosomes suppressed lep expression and reduced pe occurrence, while downregulation of mi r-18b-3p had contrary effects.Downregulated lep reversed the effect of mi r-18b-3p reduction on pe rats.Huc mscs-derived exosomal mi r-18b-3p targets lep to participate in the occurrence and development of pe.This study may provide a novel theoretical basis for the mechanism and investigation of pe.

Journal: Discover Nano (formerly known as Nanoscale Research Letters) (2021)
Publication types: Research Article;
miR-30d-5p suppresses proliferation and autophagy by targeting ATG5 in renal cell carcinoma

Previous reports have shown that mi r‐30d‐5p functions as a tumor suppressor in prostate cancer and gallbladder carcinoma, but its role in renal cell carcinoma (rcc) remains elusive.This study was designed to explore the functional role of mi r‐30d‐5p in proliferation and autophagy of rcc.Our results show that mi r‐30d‐5p is significantly down‐regulated in rcc tissues compared with normal tissues.Mi r‐30d‐5p overexpression suppressed cell proliferation, cell‐cycle g1/s transition and autophagy, but promoted apoptosis in rcc cell lines (786‐o and achn).Intriguingly, autophagy‐related gene 5 (atg5) was directly targeted by mi r‐30d‐5p, as shown using luciferase reporter assay and biotin‐avidin pull‐down assay.Moreover, overexpression of atg5 attenuated the inhibitory effect of mi r‐30d‐5p on proliferation and autophagy in 786‐o cells.These results suggest that mi r‐30d‐5p suppresses proliferation and autophagy in rcc cells by targeting atg5, and this pathway may be a suitable basis for the design of novel cancer therapeutics.

Journal: FEBS Open Bio (2020)
Publication types: Research Article;
MicroRNA-519a promotes proliferation and inhibits apoptosis of hepatocellular carcinoma cells by targeting FOXF2

Recent studies report that micro rna‐519a (mi r‐519a) is a novel oncomir, which facilitates the onset and progression of human cancers.However, the clinical significance of mi r‐519a and its functional role and underlying mechanisms in hepatocellular carcinoma (hcc) are poorly investigated.In the present study, elevated expression of mi r‐519a was observed in hcc tissues compared with adjacent non‐tumor tissues.The increased level of mi r‐519a expression was significantly correlated with adverse clinical features of hcc including hepatitis b virus (hbv) infection, large tumor size, cirrhosis and advanced tumor‐node‐metastasis tumor stage.Furthermore, high expression of mi r‐519a was prominently associated with a poorer 5‐year overall survival and recurrence‐free survival of hcc patients.Gain‐ and loss‐of function experiments showed that mi r‐519a overexpression enhanced proliferation and reduced apoptosis of huh7 cells.By contrast, mi r‐519a knockdown inhibited smmc‐7721 cell proliferation and induced apoptosis.Importantly, up‐regulation of mi r‐519a reduced the expression of foxf2 m rna and protein in huh7 cells, while down‐regulation of mi r‐519a resulted in increased expression of foxf2 in smmc‐7721 cells.An inverse correlation between m rna levels of mi r‐519a and foxf2 was observed in hcc tissues.Thus, forkhead box f2 (foxf2) was identified as a downstream target of mi r‐519a in hcc.Mechanistically, the effects of mi r‐519a knockdown on smmc‐7721 cells were abrogated by foxf2 repression.In conclusion, mi r‐519a is a novel prognostic predictor for hcc patients and it may potentiate proliferation and inhibits apoptosis of hcc cells by targeting foxf2.

Journal: FEBS Open Bio (2015)
Publication types: Research Article;
Restored microRNA-326-5p Inhibits Neuronal Apoptosis and Attenuates Mitochondrial Damage via Suppressing STAT3 in Cerebral Ischemia/Reperfusion Injury

Studies have greatly explored the role of micro rnas (mi rnas) in cerebral ischemia/reperfusion injury (ci/ri).But the specific mechanism of mi r-326-5p in ci/ri is still elusive.Hence, this study was to unmask the mechanism of mi r-326-5p/signal transducer and activator of transcription-3 (stat3) axis in ci/ri.Two models (oxygen and glucose deprivation [ogd] in primary rat cortical neurons and middle cerebral artery occlusion [mcao] in sprague–dawley rats) were established to mimic ci/ri in vitro and in vivo, respectively.Loss- and gain-of function assays were performed with ogd-treated neurons and with mcao rats.Afterward, viability, apoptosis, oxidative stress and mitochondrial membrane potential in ogd-treated neurons were tested, as well as pathological changes, apoptosis and mitochondrial membrane potential in brain tissues of mcao rats.Mitofusin-2 (mfn2), mi r-326-5p and stat3 expression in ogd-treated neurons and in brain tissues of mcao rats were detected.Mfn2 and mi r-326-5p were reduced, and stat3 was elevated in ogd-treated neurons and brain tissues of mcao rats.Mi r-326-5p targeted and negatively regulated stat3 expression.Restoring mi r-326-5p or reducing stat3 reinforced viability, inhibited apoptosis and oxidative stress, increased mitochondrial membrane potential and increased mfn2 expression in ogd-treated neurons.Up-regulating mi r-326-5p or down-regulating stat3 relieved pathological changes, inhibited apoptosis and elevated mitochondrial membrane potential and mfn2 expression in brain tissues of rats with mcao.This study elucidates that up-regulated mi r-326-5p or down-regulated stat3 protects against ci/ri by elevating mfn2 expression.

Journal: Discover Nano (formerly known as Nanoscale Research Letters) (2021)
Publication types: Research Article;
Isovitexin modulates autophagy in Alzheimer's disease via miR-107 signalling

Background: alzheimer’s disease (ad) is an ultimately fatal, degenerative brain disease in the elderly people.In the current work, we assessed the defensive capability of isovitexin (ivx) through an intracerebroventricular injection of streptozotocin (stz)-induced ad mouse model.Methods: mice were separated into four cohorts: sham-operated control mice; stz-intoxicated alzheimer’s mice; ivx cohort, ivx + stz; and ant-107 cohort, antagomi r-107 + ivx/stz as in the ivx cohort.Results: the outcomes indicated that ivx administration ameliorated spatial memory loss and blunted a cascade of neuro-noxious episodes – including increased amyloid-beta (aβ) and degraded myelin basic protein burden, neuroinflammation (represented by elevated caspase-1, tnf-α and il-6 levels) and autophagic dysfunction (represented by altered lc3-ii, atg7 and beclin-1 expressions) – via the inhibition of pi3k/akt/m tor signalling axis.We considered the question of whether the epigenetic role of micro rna-107 (mi r-107) has any impact on these events, by using antagomi r-107.Conclusion: this probing underscored that mi r-107 could be a pivotal regulatory button in the activation of molecular signals linked with the beneficial autophagic process and anti-inflammatory activities in relation to ivx treatment.Hence, this report exemplifies that ivx could guard against aβ toxicity and serve as an effectual treatment for patients afflicted with ad.

Journal: Translational Neuroscience (2020)
Publication types: Research Article;
siRNA-mediated knockdown against NUF2 suppresses pancreatic cancer proliferation in vitro and in vivo

Nuf2 (nuf2, ndc80 kinetochore complex component) plays an important role in kinetochore-microtubule attachment.It has been reported that nuf2 is associated with multiple human cancers.However, the functional role of nuf2 in pancreatic cancer remains unclear.In this study, we found that nuf2 expression was stronger in tumour tissues than in normal pancreatic tissues, and its overexpression could be related to poor prognosis.Moreover, nuf2 was highly expressed in several human pancreatic cancer cell lines.We took advantage of lentivirus-mediated si rna (small interfering rna) to suppress nuf2 expression in panc-1 and sw1990 cell lines aiming to investigate the role of nuf2 in pancreatic cancer.Nuf2 silencing by rani (rna interference) reduced the proliferation and colony formation ability of pancreatic cancer cells in vitro.Cell cycle analysis showed that nuf2 knockdown induced cell cycle arrest at g0/g1 phase via suppression of cyclin b1, cdc2 and cdc25a.More importantly, nuf2 silencing was able to alleviate in vivo tumourigenesis in pancreatic cancer xenograft nude mice.Collectively, the present study indicates that the si rna-mediated knockdown against nuf2 may be a promising therapeutic method for the treatment of pancreatic cancer.

Journal: Bioscience Reports (2015)
Publication types: Research Article;