bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 540: β-Catenin/LIN28B promotes cell proliferation of human trophoblast cells via let7a repression
Authors: Wu Jing , Luan Baoxin , Yu Huandi , Yu Yinhua , Xu Congjian , Zhao Hongbo 
Published: August 2018

Abstract
LIN28 is a highly conserved RNA-binding proteins, have been implicated in key biological functions such as development, glucose metabolism and pluripotency. LIN28 overexpression induces the reprogramming of pluripotent stem cells (iPSCs) and supports the proliferative and metabolic capacities of iPSCs. Therefore LIN28 is crucial for the regulation of the cell fate and human embryonic development. In addition, LIN28B is frequently up-regulated in a variety of cancers and correlates with poor prognosis and cancer recurrence, indicating the crucial role of LIN28B in tumorigenesis. Aberrantly expression of LIN28B is responsible for the decrease in the let-7 microRNA family observed in many cancers and Let-7 is frequently down-regulated in numerous different tumors and lower levels of let-7 correlates with poor prognosis. Therefore, LIN28/Let7 may be crucial for the regulation of cell cycle and cell proliferation. In our present study, We first detected the expression of LIN28B in normal placental villi and choriocarcinoma tissue. Our data showed LIN28B was highly expressed in human choriocarcinoma tissues and most LIN28B staining was localized in the nucleus. Comparatively, LIN28B staining was faint in normal placental villi. Our data then demonstrated that LIN28B was highly expressed in human choriocarcinoma cell lines JEG-3 and JAR. However, LIN28B expression was undetectable in HTR-8/Svneo normal trophoblast cells. Our data then demonstrated that LIN28B knockdown by small interfering RNA (siRNA) caused an increase in Let-7a expression. Further, silencing of LIN28 inhibited IGF2BP1 expression and suppressed cell proliferation capacity, which can be markedly restored by Le7a siRNA. These findings reveal that LIN28 may promote IGF2BP1 expression and cell proliferation by Let-7a repression. Moreover, β-catenin knockdown resulted in reduced LIN28 expression and Let-7a up-regulation. β-catenin is the major mediator of canonical Wnt signaling pathway, and activation of canonical Wnt signaling has been reported to play a critical role in the proliferation, invasion, and differentiation of various tumors. Collectively, our present data indicated that β-catenin/LIN28B/Let7a pathway may be crucial for cell proliferation regulation in human choriocarcinoma cells.
Citation Format: Jing Wu, Baoxin Luan, Huandi Yu, Yinhua Yu, Congjian Xu, Hongbo Zhao. β-Catenin/LIN28B promotes cell proliferation of human trophoblast cells via let7a repression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 540.
Abstract 541: Involvement of miRNA expression may contribute for FoxO3a oncogenic role in uterine leiomyosarcoma
Authors: Garcia Natalia , Ricci Anamaria Ritti , Almeida Bruna Cristine de , Almeida Thais Gomes , Cunha Isabela Werneck , Baracat Edmund Chada , Carvalho Kátia Candido 
Published: August 2018

Abstract
Introduction: Leiomyoma (LM) and leiomyosarcoma (LMS) are uterine mesenchymal tumors that present variable clinical behavior. LM are extremely common estrogen and progesterone dependent benign tumors. On the other hand, LMS are rare and aggressive malignant tumors with limited available treatment options. FoxO3a seems to have a tumor suppressor role and its loss of function may determine deregulation in the cell proliferation, with DNA damage accumulation. Several studies demonstrated FoxO3a with an important role in several tumors development; however, its regulation or function is unknown in uterine mesenchymal tumors. Objective: Here, our goals were to assess the FoxO3a expression profile in uterine LM and LMS, to evaluate the mechanisms involved on FoxO3a regulation, and to assess its use as a marker for diagnosis, prognosis and malignancy risk prediction. Methods: Formalin-Fixed Paraffin-Embedded tissues of 56 leiomyosarcomas (LMS), 80 leiomyomas (LM) and 20 myometrium (MM) from patients, were used for FOXO3a protein evaluation by immunohistochemistry (IHQ). Epigenetic regulation of FoxO3a expression was assessed by 84 miRNAs gene analysis, using Real Time PCR method (MIHS 109Z, Qiagen). MM, LM and LMS cells were evaluated for FoxO3a gene expression by Real Time PCR. Results: FOXO3a protein showed an increased expression profile in MM, LM and LMS. Higher protein levels were observed in the comparison between LMS and MM (p&lt;0,05). Gene expression analysis corroborate the protein data, with higher FoxO3a expression in LMS compared to MM and LM cells. Concerning the miRNAs analysis, we found oncogenic has-96-5p and has-155-5p overexpressed in LMS samples (p=0,008 and p=0,0007; respectively), while the tumor suppressor miR-let7c-5p was down expressed (p=0.0026). Conclusion: FoxO3a seems to display an oncogenic role in uterine tumors and could participate in the tumors risk of malignancy. miRNAs expression profile corroborates the FoxO3a negative regulation in these tumors. However, further studies are necessary for the understanding of the FoxO3a role in LM and LMS biology.
Citation Format: Natalia Garcia, Anamaria Ritti Ricci, Bruna Cristine de Almeida, Thais Gomes Almeida, Isabela Werneck Cunha, Edmund Chada Baracat, Kátia Candido Carvalho. Involvement of miRNA expression may contribute for FoxO3a oncogenic role in uterine leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 541.
Abstract 5430: Evaluating a novel phytobiologic mixture against breast cancer cell lines: Effect on glycolytic enzymes and EMT gene expression profile
Authors: Alamoudi Aliaa A. , Alqarni Afnan A. , Ajabnoor Ghada , Niedwiecki Aleksandra , Rath Matthias , Harakeh Steve M. , Al-Abd Ahmed M. 
Published: August 2018

Abstract
Background: Recently, there has been a growing evidence proposed regarding role of phytobiological compounds against various malignancies. One of the novel phytobiological mixture (PB), which is a mixture composed of the following: quercetin, resveratrol, cruciferex, epigallocatechin-3-gallate and curcumin at different proportions. To the best of our knowledge, this is the first study to evaluate the effects of a PB on breast cancer cell lines and its impact on the expression profile of these cells.
Aim: Herein, we investigated the anti-proliferative effects of PB against two breast cancer cell lines: MDA-MB-231 and MCF-7, in addition, to investigating whether PB may alter the expression profile of glycolytic enzymes and epithelial mesenchymal transition (EMT) genes in these cell lines.
Method: The anti-proliferative effect of PB was evaluated in vitro against MCF-7 and MDA-MB-231 cell lines using SRB assay. The effect of PB on the relative expression profile of some of the glycolytic enzymes and EMT genes was conducted using TaqMan gene expression assays via reverse transcription-quantitative PCR (RT-qPCR).
Results: At 72 hrs, treatment with PB showed cytotoxic effects against MDA-MB-231 and MCF-7 cells with an IC50's of 25.9±3 µg/ml and 29.5± 0.9 µg/ml, respectively. At 24 hrs post PB treatment, there was a significant increase in the gene expression of most glycolytic enzymes such as; Phosphofructokinase muscle type (PFKM) (1.4± 0.1, p&lt;0.01) and Pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1) (1.6± 0.2 fold, p&lt; 0.001). PB did not seem to alter the EMT gene expression profile with both cadherin 1 and 2 showing no significant changes. Interestingly, however, a significant up-regulation was seen with ZEB2 member of the zinc finger E-box binding homeobox 2, post PB treatment.
Conclusion: In conclusion PB showed a promising anti-proliferative effect against two breast cancer cell lines. However, we postulate that the drug could be modulating glycolytic enzymes expression, which ultimately can affect key molecules in cell differentiation. Further studies are needed to elucidate the exact underlying mechanism and to better understand the most beneficial drug combinations that can work synergistically with PB to interfere with different tumor hallmarks.
Citation Format: Aliaa A. Alamoudi, Afnan A. Alqarni, Ghada Ajabnoor, Aleksandra Niedwiecki, Matthias Rath, Steve M. Harakeh, Ahmed M. Al-Abd. Evaluating a novel phytobiologic mixture against breast cancer cell lines: Effect on glycolytic enzymes and EMT gene expression profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5430.
Abstract 5446: Serotonin modulates AKT-mTOR and Notch signaling pathways, promotes liver cancer cell steatosis and cell survival
Authors: Niture Suresh , Kumar Deepak 
Published: August 2018

Abstract
The hormone serotonin is known as 5-hydroxytryptamine. It is a precursor of melatonin, derived from the amino acid tryptophan. Serotonin acts as a neurotransmitter and modulates several key functions in the human body, such as appetite, mood and sleep. Apart from its important roles in the central nervous system (CNS), serotonin regulates various extra-neuronal pathophysiological functions. Serotonin is synthesized by Enterochromaffin cells of the gut, mostly stored in platelets and about 2% of free serotonin released in the blood. The role of peripheral serotonin in adipocytes, pancreatic cells, macrophages and liver cells is not fully understood. In the current study, we investigated the role of serotonin in liver cancer cell signaling and liver cancer cell growth. Treatment of serotonin in liver cancer cells HepG2 and SK-Hep1 induced autophagy markers and effectors such as LC3 I/II, phospho-4EBP1, ATG3 and Beclin1, and, increased cell proliferation and cell survival. AKT/mTOR pathway controls cellular autophagy and our results demonstrated that exposure of serotonin to liver cancer cells inactivates AKT/mTOR signaling and induced autophagy. Also, we demonstrate that serotonin also activates Notch signaling pathway as evident by induction of Notch target gene Hes1. Notch inhibitors Avagacestat 2 and FLI-06 inhibited serotonin-mediated Notch signaling and cellular autophagy. Furthermore, by the activation of Notch signaling, serotonin-induced oleic acid-mediated cell steatosis in both HepG2 and SK-Hep1 liver cancer cells. In addition, treatment of serotonin also induced autophagy modulator proteins such as SIRT1 and Tumor Necrosis Factor Alpha Inducing Protein 8 (TNFAIP8) which participate in the modulation of cellular autophagy and cell survival. Taken together our data suggested that peripheral serotonin regulates liver cancer cell steatosis, cells survival and may promote liver carcinogenesis by the modulation of AKT/mTOR and Notch signaling pathways.
Citation Format: Suresh Niture, Deepak Kumar. Serotonin modulates AKT-mTOR and Notch signaling pathways, promotes liver cancer cell steatosis and cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5446.
Abstract 5464: Pharmacologic activation of REV-ERBs is lethal in cancer and oncogene-induced senescence
Authors: Sulli Gabriele , Rommel Amy , Wang Xiaojie , Kolar Matthew J. , Puca Francesca , Saghatelian Alan , Plikus Maksim V. , Verma Inder M. , Panda Satchidananda 
Published: August 2018

Abstract
The circadian clock drives daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response. Perturbations of these processes are hallmarks of cancer, and circadian rhythm disruption predisposes to tumor development in animal models and humans. This raises the hypothesis that pharmacologic modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. The nuclear hormone receptors REV-ERBα and REV-ERBβ (REV-ERBs) are essential components of the circadian clock. Here we show that SR9009 and SR9011, two different agonists of REV-ERBs, are specifically lethal to cancer cells and oncogene-induced senescent (OIS) cells, including melanocytic naevi, while having no effect on viability of normal cells or tissues. Anticancer activity of SR9009 and SR9011 affects several oncogenic drivers (such as H-RAS, BRAF, PIK3CA, and others), and persists in the absence of p53 and under hypoxic conditions. The regulation of autophagy and de novo lipogenesis by SR9009 and SR9011 plays a critical role in evoking an apoptotic response in malignant cells. Importantly, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing any overt toxicity in mice. These results indicate that pharmacologic modulation of circadian regulators is an effective novel antitumor strategy, identifying the existence of a previously unknown class of anticancer agents with a wide therapeutic window. We propose that REV-ERB agonists are novel autophagy and de novo lipogenesis inhibitors with selective activity towards malignant and benign neoplasms.
Citation Format: Gabriele Sulli, Amy Rommel, Xiaojie Wang, Matthew J. Kolar, Francesca Puca, Alan Saghatelian, Maksim V. Plikus, Inder M. Verma, Satchidananda Panda. Pharmacologic activation of REV-ERBs is lethal in cancer and oncogene-induced senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5464.
Abstract 5480: Colorectal cancer cell lines harboring mutation in Wnt/β-catenin pathway shows enhanced sensitivity to the stearoyl-CoA desaturase (SCD) inhibitor, DSP-0692
Authors: Furuta Yudai , Fukunaga Yuichi , Ikeda Satoshi , Koga Erina , Umehara Hiroki , Otsubo Tsuguteru , Watanabe Manabu , Hasegawa Futoshi , Ban Hitoshi , Sugaru Eiji 
Published: August 2018

Abstract
Colorectal cancer (CRC) is one of the most frequent malignant diseases worldwide. Recent studies suggest that a small subpopulation of cells known as cancer stem cells (CSCs) may promote the high metastasis and relapse associated with CRC. It has been reported that Wnt/β-catenin signaling is aberrantly activated in a variety of cancer including colorectal cancer, and plays a critical role in CSC maintenance.
Here it is shown that a novel SCD inhibitor, DSP-0692, may inhibited Wnt/β-catenin signaling pathway through two different mechanisms in CRC. The effect of SCD inhibition on Wnt3A secretion, in which process post-translational fatty acylation (with palmitoleic acid) is required, was investigated. DSP-0692 led to reduced Wnt3A protein levels secreted in the media in Wnt3A-overexpressing cell line. This result was further confirmed by the TCF/LEF reporter assay in HCT116 incubated with conditional media from L-Wnt3A cells, with or without DSP-0692. DSP-0692 also inhibited exogenous Wnt3A-induced reporter activity. This indicates DSP-0692 may inhibit the β-catenin/Tcf transactivation by additional mechanism in addition to inhibiting Wnt secretion. To clarify this additional mechanism, the effect of DSP-0692 on nuclear translocation of β-catenin was investigated. SCD inhibition led to a decrease of β-catenin amounts within the nucleus. Currently, how SCD inhibition affects nuclear translocation of β-catenin is being investigated. It was confirmed that DSP-0692 exhibited lower IC50 value to sphere cells carrying mutations related to Wnt/β-catenin signaling pathway than those without these mutations. Next, the effect of SCD inhibition on Wnt/β-catenin signaling pathway in vivo was investigated. Treatment with DSP-0692 in a SW620 colorectal cancer xenograft model suppressed mRNA expression of the Wnt/β-catenin target genes, as well as CSC marker gene.
Taken together, these results suggest fatty acid desaturation in tumor cells may have an impact on Wnt/β-catenin signaling pathway and involve in CSC maintenance. The approaches targeting SCD could be a new therapeutic strategy for anti-CSC therapy in CRC.
Citation Format: Yudai Furuta, Yuichi Fukunaga, Satoshi Ikeda, Erina Koga, Hiroki Umehara, Tsuguteru Otsubo, Manabu Watanabe, Futoshi Hasegawa, Hitoshi Ban, Eiji Sugaru. Colorectal cancer cell lines harboring mutation in Wnt/β-catenin pathway shows enhanced sensitivity to the stearoyl-CoA desaturase (SCD) inhibitor, DSP-0692 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5480.
Abstract 5495: Inhibiting ERRα blocks liver steatosis and tumorigenesis induced by PTEN loss
Authors: Chen Chien-Yu , Li Yang , Chen Jingyu , He Lina , Stiles Bangyan 
Published: August 2018

Abstract
Mitochondrial dysfunction has been attributed to be a major cause for fatty liver development and also underlies tumor development. Using a liver-conditional Pten deletion model where the activation of its downstream PI3K/AKT signaling led to fatty liver, steatohepatitis, fibrosis and finally liver cancer development, we reported previously that the fatty liver and liver cancer is accompanied by elevated mitochondrial bioenergetics and a dramatic induction of estrogen-related receptor α (ERRα), a master regulator that orchestrate mitochondria response to modulate metabolism. In this project, we intended to investigate whether blocking ERRα expression and inhibiting mitochondrial respiration can attenuate tumor growth and lipid accumulation in the Pten null livers and human liver cancer cells. Using a genetic knockdown approach with siERRα and chemical genomic approach with a small molecular polyamide compound that binds to the ERRα consensus binding site, we showed that ERRα knockdown suppressed mitochondrial function and impeded cell proliferation in human liver as well as prostate cancer cell lines lacking Pten. In addition, blocking ERRα transcriptional activity with ERRα specific polyamide err-PA significantly reduced tumor growth in xenograft models. Furthermore, err-PA administration in vivo in 1.5-month old liver- specific Pten null mice remarkably prevented the development of fatty liver morphology and quantitatively reduced the hepatic triglyceride level. In summary, our study highlights ERRα's crucial role in regulating mitochondrial bioenergetics and underscores its therapeutic potential in cancer and lipid disorders.
Citation Format: Chien-Yu Chen, Yang Li, Jingyu Chen, Lina He, Bangyan Stiles. Inhibiting ERRα blocks liver steatosis and tumorigenesis induced by PTEN loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5495.
Abstract 5502: Characterization of a hotspot PTEN mutation in endometrial cancer
Authors: Wang Ye , Jakubik Charles , Peterson Rachel , Benes Cyril , Haas Wilhelm , Engelman Jeffrey , Costa Carlotta 
Published: August 2018

Abstract
Endometrial cancer is the most common gynecologic malignancy in the developed world. These cancers harbor the highest rates of PI3K pathway alterations reported, with PTEN being the most frequently altered gene. Differently from other cancer types, in endometrial cancer a specific hotspot mutation in the lipid phosphatase domain of PTEN is present at residue 130. This hotspot mutation significantly co-occurs with other mutations in the PI3K pathway, such as PIK3CA and PIK3R1. Interestingly, in the TCGA data we also found a positive correlation between this mutation and the expression level of the estrogen receptor alpha. Although it has been reported that the PTEN-R130 mutant loses its lipid phosphatase activity in vitro, little is known regarding the other unconventional functions of PTEN, such as its protein phosphatase activity. We performed unbiased phospho-proteomics experiments in order to explore the impact of this specific mutation in multiple endometrial cancer cell models.
Citation Format: Ye Wang, Charles Jakubik, Rachel Peterson, Cyril Benes, Wilhelm Haas, Jeffrey Engelman, Carlotta Costa. Characterization of a hotspot PTEN mutation in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5502.
Abstract 5512: Dual inhibition of AXL and FN14 reverses cisplatin resistance in non-small cell lung carcinoma by inducing higher caspase 3 cleavage
Authors: Mukherjee Soumavo , Suresh Dhananjay , Zambre Ajit P. , Upendran Anandhi , Kannan Raghuraman 
Published: August 2018

Abstract
Background and Objectives: NSCLC patients undergoing Cisplatin therapy often develop resistance within 9-12 months that decreases treatment efficacy and is the major reason for the low median survival of 10-14 months among stage IV patients. Therefore, resistance is the main therapeutic limitation in the later part of the progressive disease. It has been suggested that suppressed Caspase-3 is one of the major reasons for failure to induce apoptosis by the cell during cisplatin resistance. We hypothesized this resistance to be related to EMT and other survival pathways. Recently, AXL and TWEAK/FN14 pathways have been shown to be upregulated in cisplatin resistant cells causing activation of EMT and survival pathways. Therefore, we examined whether dual inhibition of AXL and TWEAK/FN14 successfully reverses the cisplatin resistance in NSCLC.
Materials and Methods: Drug resistant EGFR mutant H1975 and KRAS mutant A549 cells were tested for cisplatin desensitization following knock down of AXL and FN14 inhibition. We studied resensitization by determining the IC50 values in the drug resistant cell lines by treatment with both AXL and FN14 siRNA. We investigated detailed cellular mechanisms imparting resistance by detecting relative levels of Caspase 3, cleaved Caspase 3, PARP, cleaved PARP, p-SRC, p-EGFR, AXL and FN14 by western blotting. Cytochrome-C induced apoptosis was detected by monitoring cytochrome-c released from mitochondria using fluorescence microscopy.
Results: Suppression of AXL and FN14 by siRNA treatment resensitized NSCLC to cisplatin and induced apoptosis. IC50 values were decreased significantly following dual inhibition (by more than 200%). A marked increase in cleaved caspase 3 levels was also observed in both mutant cell lines. A subsequent increase in PARP and cleaved PARP levels verified the fact that caspase 3 is indeed responsible for the apoptosis in these cells. Upregulation of p-SRC and eventually p-EGFR failed to suppress the apoptosis through PI3K/AKT pathway. Cytochrome c release from mitochondria further confirmed cellular apoptosis.
Conclusion: Our results show that dual inhibition of AXL and TWEAK/FN14 can reverse cisplatin resistance by inducing higher caspase 3 cleavage that can enhance survival of NSCLC patients undergoing chemotherapy.
Citation Format: Soumavo Mukherjee, Dhananjay Suresh, Ajit P. Zambre, Anandhi Upendran, Raghuraman Kannan. Dual inhibition of AXL and FN14 reverses cisplatin resistance in non-small cell lung carcinoma by inducing higher caspase 3 cleavage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5512.