tbuckley/cabot-search huggingface dataset:
Abstract 3446: Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT-mediated HIF-1α inactivation
Authors: Tong Hong Wang, Chi Hao Wu, Chau Ting Yeh, Kung Hao Liang, Chuen Hsueh, Chi Yuan Chen
Journal: Cancer Research (2017)

Abstract Background: Melatonin, the main pineal hormone that relays light/dark cycle information to the circadian system, was recently reported to have intrinsic antitumor activity in various cancers. However, the detailed regulatory mechanisms associated with antitumor activity of melatonin are not well understood yet. Moreover, limited studies have addressed the role of melatonin in hepatocellular carcinoma (HCC), the major life-threatening malignancy for both sexes in Taiwan. Hence, in this study, we investigated the antitumor activity of melatonin on HCC and explored its regulatory mechanism. Methods: Human hepatoma cell lines HepG2 and Huh7 were treated with melatonin followed by functional assays to dissect antitumor effect of melatonin in HCC. The whole transcriptome sequence analysis was performed to explore the long non-coding RNAs (lncRNAs) involved in the anti-HCC activity of melatonin. Further, quantitative RT-PCR, western blot, immunohistochemistry assays, and in vivo animal model experiments were performed to elucidate the regulatory mechanism of lncRNAs in melatonin-mediated HCC suppression. Results: Melatonin significantly inhibited cell proliferation, migration, and invasion capacity of HCC cell lines, while the expression of transcription factor FOXA2 was significantly induced in cells treated with melatonin. The increase in expression of FOXA2 resulted in upregulation of lncRNA-CPS1-IT1 expression, which in turn reduced binding and activation of Hsp90 with HIF-1α. The inactivation of HIF-1α resulted in the suppression of epithelial-mesenchymal transition (EMT) progression and HCC metastasis. Furthermore, the results of the in vivo animal model experiments also validated the tumor-suppressor role of melatonin via a reduction in tumor growth. Conclusions: Taken together, our findings suggested that melatonin inhibited HCC progression by modulating lncRNA-CPS1-IT1-mediated EMT suppression and further supported melatonin as a promising therapeutic agent for the treatment of HCC. Note: This abstract was not presented at the meeting. Citation Format: Tong Hong Wang, Chi Hao Wu, Chau Ting Yeh, Kung Hao Liang, Chuen Hsueh, Chi Yuan Chen. Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT-mediated HIF-1α inactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3446. doi:10.1158/1538-7445.AM2017-3446
Abstract 1284: Identification of potential cancer regulatory germline single-nucleotide polymorphisms in the non-coding genome
Authors: Diptee A. Kulkarni, Kijoung Song, Karl Guo
Journal: Cancer Research (2017)

Abstract Tumorigenesis in sporadic cancers is mainly driven by somatic genetic alterations such as driver mutations in protein coding genes or chromosomal changes comprising deletions, amplifications or translocations resulting in loss of tumor suppressor proteins, gain of oncogenic proteins or expression of aberrant fusion proteins, respectively. Some cancers lack such somatic changes, but are addicted to expression of certain genes for their sustained proliferation and survival. There is evidence of such oncogenic addiction to LIM domain only 1 (LMO1) expression in neuroblastoma (NB). Genome-wide association studies (GWAS) have identified robust associations between germline single-nucleotide polymorphisms (SNPs) within LMO1 and NB susceptibility with the causal SNP being rs2168101. Investigation of the mechanism of NB dependency on LMO1 showed that LMO1 expression in NB cells is regulated by rs2168101, which resides within a highly conserved tissue-specific super enhancer in LMO1 intron 1 and drives LMO1 expression through GATA3 transcription factor binding. This makes LMO1-dependent NB a unique example of sporadic cancer driven by germline genetic variation. Numerous GWAS have identified significant associations between germline SNPs in the non-coding genome and cancer risk or outcomes. To identify additional examples of regulatory SNPs as cancer drivers, we merged published genome-wide significant associations from cancer GWAS with genome regulatory data from ENCODE (Encyclopedia of DNA Elements; Nature. 2012 Sep 6; 489 (7414): 57-74)) and searched for clusters of cancer associated SNPs that resided within gene regulatory elements. Gene regulatory elements were defined as those marked by active epigenetic features and chromatin accessibility in cancer cell lines. Of the ~1,600 unique, genome-wide significant SNPs from cancer GWAS with regulatory evidence, we identified 46 clusters of 3 or more putative regulatory SNPs near 28 genes. These clusters were particularly enriched within ovarian cancer associated loci. Mechanistic studies such as reporter assays and genome editing in relevant cell types are being considered to identify the causal SNPs from these clusters regulating gene expression and driving tumorigenesis, which in turn may lead us to new cancer targets. Citation Format: Diptee A. Kulkarni, Kijoung Song, Karl Guo. Identification of potential cancer regulatory germline single-nucleotide polymorphisms in the non-coding genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1284. doi:10.1158/1538-7445.AM2017-1284
Abstract 5407: Integrated analysis of genome-wide microRNA and mRNA profiling reveals unregulated miR-125b associated with poor prognosis by reducing cell apoptosis in gastric cancer
Authors: Ben Liu, Da Yang, Fengju Song, Xining Zhang, Yan Guo, Yanrui Zhao, Hong Zheng, Wei Zhang, Kexin Chen
Journal: Cancer Research (2017)

Abstract Background &amp; Aims: In our prior study, an integrated analysis of microRNA and mRNA profiling of gastric cancer (GC) revealed a mRNA-regulatory network. It defined a GC microRNA subtype that was associated with poor survival in 90 GC cases. In this study, we further demonstrate that miR-125b, a key node in this microRNA regulatory network, is upregulated in GC and associated with poor overall survival by interfering in the apoptosis pathway. Methods: To further investigate the role of miR-125b in GC, we conducted both an in vitro experiment and clinical study (cohort of 373 GC samples). miR-125b and targets in the network were validated through RT-PCR and tissue microarray GC cases. The miR-125b targeted gene and related pathway were identified by a gene expression profile analysis in miR-125b transfected GC cell lines. The Annexin V-FITC and TUNEL assay were used to assess apoptosis. MTT and flow cytometry were performed to detect the effect of miR-125b on proliferation and cell cycle. The wound healing test and transwell assay were used to analyze migration and invasion. Results: The markly upregulated expression of miR-125b was validated in 373 GC samples.. Univariate and multivariate analyses find that the miR-125b was associated with poor prognosis (p=0. 011). Pathway analysis shows that the predicted targets of miR-125b are highly involved in apoptosis/program death pathway. The robust apoptosis genes, BIK and CASP6 are validated as the directed targets of miR-125b. miR-125b can suppress apoptosis and increas cell growth, migration and invasion in GC cell lines. Furthermore, low expression of BIK (p=0. 034) and CASP6 (p=0.048) in GC were associated with poor disease-free survival. Conclusions: The apoptosis pathway was found to be dominant in the pathway construction based on target genes of miR-125b. Our findings suggest that miR-125b-regulated apoptosis pathway is important to GC progression and that the miR-125 may be an important clinical biomarker for GC survival and possible therapeutic target for GC treatment. Citation Format: Ben Liu, Da Yang, Fengju Song, Xining Zhang, Yan Guo, Yanrui Zhao, Hong Zheng, Wei Zhang, Kexin Chen. Integrated analysis of genome-wide microRNA and mRNA profiling reveals unregulated miR-125b associated with poor prognosis by reducing cell apoptosis in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5407. doi:10.1158/1538-7445.AM2017-5407
Abstract 2325: Destruction of circulating tumor cells by fluid shear stresses generated in a microfluidic system
Authors: Sagar Regmi, Afu Fu, Sierin Lim, Kathy Qian Luo
Journal: Cancer Research (2017)

Abstract Circulating tumor cells (CTCs) are mainly responsible for the cause of cancer metastasis. Although most CTCs can be destroyed by the bloodstream, some of them can still manage to withstand hemodynamic shear stress in blood stream. To study the effects of fluidic micro-environment on CTCs, we designed a microfluidic system that can produce various levels of shear stress which can be generated in human artery under resting or exercise condition. We also generated three human breast cancer cell lines with increased ability to form lung metastases in nude mice (i.e. 213-M1A&amp;gt;231-M1&amp;gt;231-C3). All three cell lines can produce a fluorescence resonance energy transfer (FRET)-based sensor which can reveal apoptosis in real-time by changing its color from green to blue. Besides these, we also investigated the effects of shear stress on multiple types of cancer cells including lung cancer (A549), ovarian cancer (2008), breast cancer (UACC-893) and leukemia (K562). For all the cell lines, except the non-attached K562 cells, cells were cultured on petri-dishes, detached by trypsinization and re-suspended in a normal culture medium to a cell density of 2x105 cells/ml. One milliliter of this cell suspensions was circulated in our microfluidic system under the shear stresses of 15, 30, 45 and 60 dyne/cm2 for 2-18 h. The effects of shear stress on morphology and viability of CTCs were determined by FRET imaging microscopy and MTT assay. And the impact of shear stress on causing necrosis in CTCs were examined by propidium iodide (PI) staining and LDH assay. Our findings are summarized below: 1) High shear stress (SS60, 4 h) is more potent to destroy CTCs than low shear stress (SS15, 4 h). 2) High shear stress can destroy most of the CTCs via necrosis. 3) This high level of shear stress is theoretically achievable via physical exercise. 4) Highly metastatic 231-M1A cells are more resistant to high shear stress compared to less metastatic 231-C3 cells. 5) Leukemia K562 cells representing the white blood cells showed stronger resistance to high shear stress compared to the cancer cells tested in this study. We think these findings can help people to understand how metastatic CTCs resist shear force-induced cell death which are useful for designing more effective therapies against metastatic CTCs. Additionally, the finding that high shear stress is more effective to kill CTCs may inspire cancer patients to consider exercise as a way to increase their hemodynamic shear stress, consequently destroy CTCs and prevent cancer metastasis. Citation Format: Sagar Regmi, Afu Fu, Sierin Lim, Kathy Qian Luo. Destruction of circulating tumor cells by fluid shear stresses generated in a microfluidic system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2325. doi:10.1158/1538-7445.AM2017-2325
Abstract 5657: Objective measurement and significance of VISTA (PD-1H) expression in non-small cell lung cancer (NSCLC)
Authors: Franz Villarroel-Espindola, Ila J. Datar, Vamsidhar Velcheti, David L. Rimm, Roy S. Herbst, Kurt A. Schalper
Journal: Cancer Research (2017)

Abstract Introduction: VISTA (PD-1H) is a member of the B7 family of immune co-regulatory molecules and has been proposed as a novel anti-cancer immunotherapy target. The intra- and extracellular domains of VISTA show homology to PD-1 and PD-L1, respectively, suggesting a role in anti-tumor immune evasion. The expression of VISTA, its association with PD-1 axis components and biological role in human NSCLC are unknown. Methods: Using multiplex quantitative immunofluorescence (QIF), we simultaneously measured the levels of VISTA (clone D1L2G, CST), PD-L1 (clone 405.9A11, CST) and PD-1 (clone EH33, CST) protein in 732 stage I-IV NSCLCs from 3 retrospective collections represented in tissue microarray format (cohort #1 [n=297, Yale], cohort #2 [n=329, Greece]; and cohort #3 [n=106, Yale]). To evaluate the tumor tissue distribution, VISTA was also selectively measured in cytokeratin+ tumor cells, CD3+ T-cells, CD4+ T-helper cells, CD8+ cytotoxic T-cells and CD20+ B-lymphocytes. Associations between the marker levels, clinico-pathological-molecular variables and survival were studied. Results: VISTA protein was detected in all NSCLCs, showed a membranous staining pattern and was localized predominantly in the tumor cells in 27.4% of cases; and in the stromal compartment in 98.5%. Although VISTA was detected in all major tumor infiltrating lymphocyte (TIL) subsets, the signal was higher in CD20+ B-cells than in CD3+ T-lymphocytes (P&amp;lt;0.05); and in CD4+ helper than in CD8+ cytotoxic T-cells (P&amp;lt;0.001). Using the median score as cut point, elevated VISTA in tumor and/or stromal cells was significantly associated with high PD-L1, PD-1 protein expression and increased CD8+TILs in the cohorts (P&amp;lt;0.001 - P&amp;lt;0.05). No consistent association between VISTA levels and age, gender, smoking status, specific NSCLC histology, stage, EGFR/KRAS mutations and overall survival was found. Conclusion: VISTA is expressed in the majority of NSCLCs and shows differential distribution in tumor/stromal cells and TIL subsets, suggesting a complex function as a ligand and receptor. Elevated expression of VISTA in NSCLC is associated with increased PD-1 axis targets and cytotoxic T-cell density, indicating its possible modulation by pro-inflammatory signals. Our results support VISTA as a candidate target for anti-cancer immunotherapy in NSCLC alone or in combination with PD-1 axis blockers. Citation Format: Franz Villarroel-Espindola, Ila J. Datar, Vamsidhar Velcheti, David L. Rimm, Roy S. Herbst, Kurt A. Schalper. Objective measurement and significance of VISTA (PD-1H) expression in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5657. doi:10.1158/1538-7445.AM2017-5657
Abstract 1054: Nobiletin synergizes cytotoxicity of antimicrotubule agents by inhibiting Pin1 pathway
Authors: Kazunori Kato, Takumi Yamazaki, Masaaki Honma
Journal: Cancer Research (2017)

Abstract Nobiletin is a citrus polymethoxy flavonoid that suppresses cell proliferation, angiogenesis and metastatic properties in various cancer cells. In this study, we investigated the combined effects of nobiletin and various chemotherapeutic agents on the cytotoxicity of human colon and esophageal cancer cells. We cultured cancer cells at serial dilution of chemotherapeutic agents with or without nobiletin and assessed cell cytotoxicity at 5 days after drug treatment. The addition of a suboptimal dose of nobiletin did not alter the growth of cancer cells, however cytotoxic effect of antimetabolites (gemcitabine and 5-FU) and DNA-platinating agent (cisplatin) were markedly attenuated by nobiletin. By contrast, nobiletin markedly enhanced antitumor effect of antimicrotubule agents such as docetaxel, paclitaxel, vincristine and MMAE. Moreover, enhanced cytotoxicity by nobiletin was also verified in the combination with MMAE- or DM1-conjugated antibodies to EpCAM and EphA2. We found the inhibition of phosphorylation and nuclear translocation of Pin1 (peptidyl-prolyl isomerase) by nobiletin, suggesting a rational molecular target of nobiletin is Pin1. Overall, these data suggest that nobiletin might useful for the chemotherapeutic treatment of microtubule inhibitors. Citation Format: Kazunori Kato, Takumi Yamazaki, Masaaki Honma. Nobiletin synergizes cytotoxicity of antimicrotubule agents by inhibiting Pin1 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1054. doi:10.1158/1538-7445.AM2017-1054
Abstract 446: Differential effects of folate depletion on metabolic reprogramming and oxidative stress in nonmetastatic and metastatic claudin-low breast cancer cells
Authors: Xuewen Chen, Ciara H. O'Flanagan, Stephen D. Hursting
Journal: Cancer Research (2017)

Abstract Folate coenzymes play an important role in biosynthesis and methylation reactions. Aberrant folate metabolism has been implicated in the development of several cancer types, though mechanisms underlying folate metabolism and cancer development remain unclear. We previously showed that a folate-restricted diet can exert differential effects on metastatic versus nonmetastatic murine claudin-low breast cancer cells in vivo. Specifically, folate restriction increased growth and invasion of orthotopically transplanted M-Wnt (nonmetastatic) tumor cells, but decreased growth and lung metastases of transplanted metM-Wnt cells, a metastatic subclone of M-Wnt cells. The current study set out to explore the underlying mechanism. To examine the effect of long-term folate depletion (LFD) on M-Wnt and metM-Wnt cell metabolism, oxidative stress and autophagic flux in vitro, the two cell lines were grown in standard and folate-depleted media for 14 days. metM-Wnt cells showed higher oxidative stress, as measured by ROS staining and Nrf2 expression, and phosphorylation of the key nutrient sensor, AMPK, compared to M-Wnt cells when grown in standard growth medium. LFD M-Wnt cells showed an increased dependence on glycolysis compared to those cultured in standard medium. Both M-Wnt and metM-Wnt cells displayed a high autophagy level in LFD, measured by LC3B cleavage, and AMPK phosphorylation. However, LFD metM-Wnt cells showed low viability, increased apoptosis and loss of redox defense, as measured by cleaved-caspase 3 and Nrf2 expressions. These results suggest that non-metastatic M-Wnt cells undergo metabolic reprogramming, including a shift from oxidative phosphorylation to glycolysis that may fuel cell growth and proliferation. Further, an elevated autophagic flux may mitigate nutrient stress induced by folate depletion, which allows them to withstand LFD and which may contribute to a more invasive primary tumor in response to folate restriction. In contrast, metM-Wnt cells are unable to undergo this metabolic adaptation, and display increased oxidative stress and cell death in response to LFD, preventing the development of metastatic lesions in vitro. This study highlights different responses of primary and metastatic breast cancer cells to folate depletion. The results provide additional rationale for targeting folate metabolism as a potential strategy for treating metastatic breast cancer. Citation Format: Xuewen Chen, Ciara H. O'Flanagan, Stephen D. Hursting. Differential effects of folate depletion on metabolic reprogramming and oxidative stress in nonmetastatic and metastatic claudin-low breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 446. doi:10.1158/1538-7445.AM2017-446
Abstract LB-325: Tumor suppressor effects of miR-17-92a cluster miRNAs on prostate cancer
Authors: Ratna Chakrabarti, Richard Ottman, Md Faqrul Hasan
Journal: Cancer Research (2017)

Abstract MicroRNAs in miR-17-92a cluster are transcribed from a polycistronic transcription unit C13orf25 that generates six mature miRNAs, miR-17, miR-18a, miR-19a, miR- 19b, miR-20a. These miRNAs are reported to be overexpressed in colon and lung cancers, however, we noted a loss of expression of all members of this miR cluster in prostate cancer tissues compared to uninvolved tissues and in aggressive prostate cancer cells. In this study, we show that replenishment of miR-17-92a cluster as a whole showed antiproliferative effects, reduced activation of AKT and MAP kinases, delayed tumorigenicity and reduced tumor growth. Analysis of the expression of mRNA targets showed reduced expression of cell cycle regulatory proteins cyclin D1 and SSH1; and LIMK1 and FGD4 of RhoGTPase signaling pathway through direct targeting. miR-17-92 cluster expression also inhibited EMT via reduced cell migration and expression of mesenchymal markers while elevating expression and surface localization of the epithelial marker E-Cadherin. miR-17-92a miRNAs improved sensitivity of androgen dependent LNCaP 104-S prostate cancer cells to anti-androgen drug Casodex, AKT inhibitor MK-2206 2HCl, and docetaxel. The androgen refractory PC-3 cells also showed increased sensitivity to docetaxel, MK-2206 2HCl and Aurora kinase inhibitor VX680 upon ectopic expression of miR-17-92a cluster miRNAs. RNA seq analysis of prostate cancer cells expressing miR-17-92a cluster revealed altered expression of a number of oncogenic and tumor suppressor mRNAs, and noncoding RNAs, which may have implications in the altered phenotype of these cells. Our data demonstrate a tumor suppressor effect of miR-17-92a cluster miRNAs in prostate cancer cells and restoration of expression of these miRNAs has a therapeutic benefit for both androgen-dependent and -independent prostate cancer cells. Note: This abstract was not presented at the meeting. Citation Format: Ratna Chakrabarti, Richard Ottman, Md Faqrul Hasan. Tumor suppressor effects of miR-17-92a cluster miRNAs on prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-325. doi:10.1158/1538-7445.AM2017-LB-325