tbuckley/cabot-search huggingface dataset:
Abstract 4494: Tumor suppressive role of ZFP36L1 by suppressing HIF1α and Cyclin D1 in bladder and breast cancer
Authors: Xin Yi Loh, Ling Wen Ding, H. Phillip Koeffler
Journal: Cancer Research (2017)

Abstract AU-rich mRNAs are a class of mRNAs that contains AU-rich elements (AREs) motifs in their 3’UTR. The half-life and turnover of AU-rich mRNAs are tightly regulated by AREs-binding proteins, such as Zinc finger protein 36 C3H type-like 1 (ZFP36L1). ZFP36L1 is one of the RNA-binding proteins (RBPs), which consists of two tandemly repeated zinc finger motifs that specifically recognize AREs motifs and mediate mRNAs decay. However, our knowledge on role of ZFP36L1 in breast and bladder cancers and its downstream targets remains poorly elucidated. Here, we hypothesized that ZFP36L1 might degrade oncogenic mRNAs transcripts, thus leading to suppression of tumorigenesis. Our analysis of in silico data revealed that ZFP36L1 is significantly mutated or downregulated in a variety of cancers. The high proportion of inactivation mutation pattern as well as the Mutsig result suggest that it may act as an unappreciated tumor suppressor. Lower ZFP36L1 expression correlated with reduced survival in patients. Forced expression of ZFP36L1 markedly reduced cellular proliferation, invasiveness and migration in vitro, as well as tumor growth in vivo. In addition, microarray and RNA-seq data analysis showed that several important cancer-related candidates such as IL8 and HIF1α were significantly downregulated. Overexpression of ZFP36L1 reduced HIF1α mRNA and protein expression. Similarly, HIF1α forced expression also inhibited ZFP36L1 mRNA and protein, suggesting a feedback loop of HIF1α and ZFP36L1. Dual luciferase reporter assays and RNA Electro-mobility Shift Assay (REMSA) showed that only wild type ZFP36L1, but not different mutants of ZFP36L1, was able to bind directly and to degrade a HIF1α 3’UTR construct that contains AU-rich regions. Meanwhile, mRNA pull down assay demonstrated that ZFP36L1 protein recognized cell-cycle related transcripts. Overexpression of ZFP36L1 led to reduction of Cyclin D1 and phospho-Rb in protein expression. Furthermore, SILAC data unveiled interesting binding partners of ZFP36L1. Collectively, our findings propose that ZFP36L1 might have a critical tumor suppressive role in breast and bladder cancer by negatively regulating mRNA whose protein products cooperatively promote hypoxia and transition into S phase of cell cycle. Augmenting ZFP36L1 function might disable the cell cycle and proliferation of aggressive bladder tumors. Citation Format: Xin Yi Loh, Ling Wen Ding, H. Phillip Koeffler. Tumor suppressive role of ZFP36L1 by suppressing HIF1α and Cyclin D1 in bladder and breast 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 4494. doi:10.1158/1538-7445.AM2017-4494
Abstract 4843: ANKRD52 inhibited tumor metastasis through dephosphorylation of PAK1 in lung adenocarcinoma
Authors: Yen-Fan Lin, Ying-Pu Liu, Ting-Fang Lee, Cheng-Wen Wu
Journal: Cancer Research (2017)

Abstract As a leading cause of cancer-related deaths, metastasis is the ultimate challenge in our effort to fight cancer as a life-threatening disease. A member of ankyrin repeat proteins, ankyrin repeat domain 52 (ANKRD52), is studied here to be involved in the regulation of lung adenocarcinoma metastasis. Ankyrin repeat proteins are known to function as a platform for protein-protein interactions, and ANKRD52 was shown to interact with protein phosphatase 6 (PP6). This study aimed to investigate the anti-metastatic roles of ANKRD52 in lung adenocarcinoma. Immunohistochemistry staining in lung cancer tissue revealed prolonged disease-free survival in high ANKRD52 expressing cases. Using lung cancer cell lines, ANKRD52 knockdowns showed significantly increased cell mobility while forced expressed ANKRD52 decreased cell mobility. Using mass spectrometry analysis, p21-activated kinases (PAK1) was identified to interact with ANKRD52. Upregulated PAK1 phosphorylation was detected in ANKRD52 or PP6 knockdowns. Our model demonstrated a novel anti-metastatic protein, ANKRD52, that regulates cell mobility through interactions with PP6 and dephosphorylation of PAK1. Citation Format: Yen-Fan Lin, Ying-Pu Liu, Ting-Fang Lee, Cheng-Wen Wu. ANKRD52 inhibited tumor metastasis through dephosphorylation of PAK1 in lung adenocarcinoma [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 4843. doi:10.1158/1538-7445.AM2017-4843
Abstract 469: Microrna signature as a potential biomarker for predicting survival in colon cancer
Authors: Havjin Jacob, Luka Stanisavljevic, Kristian Eeg Storli, Olav Dahl, Mette Pernille Myklebust
Journal: Cancer Research (2017)

Abstract Background: Colon cancer is one of the most common cancers with increasing incidence and high mortality worldwide. Prognosis and choice of treatment is largely based on the tumor stage at presentation. Thus, finding novel biomarkers for predicting survival is highly desirable. Lately, several studies have been looking at microRNAs (miRNAs) in several cancers, including colon cancer. MicroRNAs are conserved, non-coding RNA molecules that play an important role in the regulation of post-transcriptional gene expression. Material and Methods: In the present study, we have profiled miRNA in one hundred and seventy two TNM stage I-IV colon cancer patients and 10 corresponding normal colon tissue samples. Total RNA was extracted from freshly frozen tissues, and the expression of miRNA profile were assessed using Pick and Mix focus panels from Exiqon containing 84 miRNAs that have been linked to cancer. Results: The results were visualized in a heatmap (Qlucore omics Software) and more than 20 miRNAs were found to be differentially expressed in tumors compared to the normal colon. Further, twelve miRNAs were found to discriminate between relapse and no-relapse patients in TNM- stage II and III, and four of these miRNAs (miR-23a, miR-25, miR-30d and miR-31) were found to be statistically significant in binary logistic regression with relapse as outcome variable. In univariate analysis, low expression of the four-miRNA signature was associated with better 3-year disease-free survival (DFS), 88 % versus 63% in low versus high signature, respectively (P=0.001). Moreover, the signature was a predictor of poor relapse-free survival in multivariate analyses (P=0.001; HR 31; 95% CI: 3.8-248.9). Another regression analyses method (LASSO) identified a 16-miRNA signature, and the four miRNAs found earlier were among them. The 16-miRNA signature was associated with better survival (P&amp;lt;0.001). Conclusion: The present study has identified a four-miRNA signature predicting relapse in colon cancer stage II and III patients. Citation Format: Havjin Jacob, Luka Stanisavljevic, Kristian Eeg Storli, Olav Dahl, Mette Pernille Myklebust. Microrna signature as a potential biomarker for predicting survival in colon 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 469. doi:10.1158/1538-7445.AM2017-469
Abstract 288: Loss of a branched actin checkpoint in cancer cells
Authors: Nicolas Molinie, Svetlana Rubtsova, Alexis Gautreau
Journal: Cancer Research (2017)

Abstract Cell proliferation depends on multiple signals, such as growth factors, adhesion to the substratum and to neighboring cells. Cancer cells proliferate independently of these signals. The same stimuli also induce actin polymerization. Here we investigate whether the actin cytoskeleton plays a role in transmitting the proliferation signal. We found that inactivation of the Arp2/3 complex by either a chemical inhibitor or by siRNAs blocks S phase entry in untransformed human breast cell lines and in primary breast epithelial cells. In contrast, breast cancer cell lines did not respond to Arp2/3 inhibition. Inactivating the tumor suppressor p21WAF1/CIP1, or Rb, converts sensitive cells into unresponsive cells further highlighting that this response to Arp2/3 inactivation is at the heart of the transformation process. The depletion of the WAVE complex, the Arp2/3 activator that generates branched actin in lamellipodia, but not of other Arp2/3 activators, blocks cell cycle progression. Conversely, activation of WAVE by active Rac, or depletion of Arpin, which antagonizes WAVE, potentiates cell cycle progression. Together, these results show that branched actin networks generated in lamellipodia are sensed and convey an essential signal for S Phase entry. The signal that branched actin delivers integrates stimulation from soluble growth factor with mechanotransduction from cell adhesions to the substratum and to neighboring cells. This signaling pathway qualifies as a checkpoint, which is required in normal cells, but lost in transformed cells, that monitors the integrity of branched actin networks and instructs the cell as a response that the required conditions to proliferate are fulfilled. Citation Format: Nicolas Molinie, Svetlana Rubtsova, Alexis Gautreau. Loss of a branched actin checkpoint in 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 288. doi:10.1158/1538-7445.AM2017-288
The &lt;italic&gt;d&lt;/italic&gt;-Peptidase Activity of Serum as an Alleged Diagnostic Test for Cancer
Authors: Mary E. Maver, J. M. Johnson, J. W. Thompson
Journal: JNCI Journal of the National Cancer Institute (1941)

The d-Peptidase Activity of Serum as an Alleged Diagnostic Test for Cancer Get access Mary E. Maver, Mary E. Maver biochemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar J. M. Johnson, J. M. Johnson senior chemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar J. W. Thompson J. W. Thompson associate pharmacologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 1, Issue 6, June 1941, Pages 835–843, https://doi.org/10.1093/jnci/1.6.835 Published: 01 June 1941
Abstract 1388: SphK2/S1P axis regulates hypoxia-mediated HIF-α synthesis in breast cancer cells
Authors: Nitai C. Hait, Aparna Maiti
Journal: Cancer Research (2017)

Abstract The hypoxia-inducible transcription factors (HIF)-1α and -2α play a critical role in cellular response to hypoxia in solid tumors. Elevated HIF-α expression correlates with poor patient survival in a large number of cancers including breast cancers. HIF-α activates expression of genes promoting angiogenesis, metastasis, increased tumor growth and resistance to treatments. Understanding transcriptional regulation HIF-α under physiologically relevant hypoxic conditions would be helpful to reduce breast cancer growth. Our recent studies identified that intracellular bioactive sphingosine-1-phosphate (S1P) generated from nuclear sphingosine kinase 2 (SphK2) acts as an endogenous modulator of histone deacetylases (HDACs) epigenetically regulates gene transcription in breast cancer cells. We wonder whether nuclear S1P epigenetically regulates acetylated histones, positive transcription marks in hypoxia and regulate transcription of HIF-α and target genes in breast cancer cells. We have used estrogen receptor positive human breast cancer MCF-7 cells, triple-negative human breast cancer MDA-231 cells, and lung metastatic LM-2-4 cells derived from MDA-231 cells cells for our studies. We found that hypoxic condition enhances nuclear bulk histone acetylation in breast cancer cells and enhances HIF-α synthesis. Down regulation of SphK2 with siRNA or using selective inhibitor of SphK2 (K145 compound) reduces nuclear S1P as well as bulk histone acetylation and consequently reduces nuclear HIF-α synthesis in breast cancer cells. Downregulation of cytosolic sphingosine kinase 1 (SphK1) with siRNA reduces cytosolic S1P does not alter nuclear bulk histone acetylation neither significantly alter nuclear HIF-α synthesis in breast cancer cells. We also found that targeting SphK2 with K145 compound dramatically reduces in vitro tumorosphere formation in breast cancer cells. Our data suggested that targeting the SphK2/S1P signaling could represent an attractive strategy for therapeutic intervention in hypoxic breast cancers. Supported by Health Research, Inc. (HRI) Grant 71-4084 (NCH), National Cancer Institute Grant R01CA160688 (KT). Citation Format: Nitai C. Hait, Aparna Maiti. SphK2/S1P axis regulates hypoxia-mediated HIF-α synthesis in 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 1388. doi:10.1158/1538-7445.AM2017-1388
Abstract 4614: Upregulation of memory T cell population and enhancement of Th1 response by lenvatinib potentiate antitumor activity of PD-1 signaling blockade
Authors: Yu Kato
Journal: Cancer Research (2017)

Abstract Introduction: Lenvatinib (LEN) selectively inhibits the kinase activity of VEGFR1-3, FGFR1-4, KIT, PDGFRα, and RET, which are involved in tumor angiogenesis and tumor cell proliferation in several cancer types. Currently, Phase 1b/2 clinical trials of the combination of LEN and pembrolizumab (a monoclonal antibody [mAb] that blocks the interaction between PD-1 and its ligands) are ongoing for selected types of cancer including renal cell carcinoma, melanoma and non-small cell lung carcinoma. We have reported that tumor associated macrophage and regulatory T cell population were downregulated by treatment of LEN. In this study, mechanism of LEN and PD-1 mAb combination was investigated by flow cytometory and RNA-seq analyses. Experimental Procedure: We examined antitumor activity of combination treatment of LEN (10mg/kg, qd) and anti-mouse PD-1 mAb (500μg/mouse, twice weekly) in Ct26 and B16F10 syngeneic mouse models. In order to investigate tumor-specific memory T cell response, re-inoculation of fresh CT26 cells into tumor-free mice was conducted. For immune cell population analyses, tumor or spleen samples were analyzed by flow cytometry. Changes of molecular immune response in tumors were examined by RNAseq followed by weighted gene co-expression network analysis (WGCNA). Summary of data: Combination of LEN with PD-1 mAb showed more potent anti-tumor growth activity in CT26 and B16F10 models compared with either treatment alone. Notably, complete tumor regression was detected in a portion of mice that received combination treatment only. Re-inoculation of fresh CT26 cells into these tumor-free mice did not grow tumor; in contrast, all naïve animals grew tumor aggressively in the same experimental condition. RNAseq analysis of treated CT26 tumors indicated that combination of LEN with PD-1 mAb synergistically up-regulates IFN signaling-related genes. Flow cytometory analysis revealed that LEN increased memory T cell population compared with vehicle treatment. Conclusions: The results indicate that the combination of LEN with PD-1 mAb was more effective than either single agent alone in multiple syngeneic tumor models and was accompanied with a potent antitumor immune response, especially the up-regulation of memory T cell and Th1 activation by LEN. Citation Format: Yu Kato. Upregulation of memory T cell population and enhancement of Th1 response by lenvatinib potentiate antitumor activity of PD-1 signaling blockade [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 4614. doi:10.1158/1538-7445.AM2017-4614
Abstract 126: A chemogenomic approach reveals the action of splicing modulators at the branch point adenosine binding pocket defined by the PHF5A/SF3b complex
Authors: Teng Teng, Jennifer Tsai, Xiaoling Puyang, Michael Seiler, Shouyong Peng, Daniel Aird, Silvia Buonamici, Benjamin Caleb, Betty Chan, Laura Corson, Jacob Feala, Peter Fekkes, Craig Karr, Manav Korpal, Yoshiharu Mizui, Eunice Park, James Palacino, Peter Smith, Vanitha Subramanian, Jeremy Wu, Lihua Yu, Agustin Chicas, Markus Warmuth, Nicholas Larsen, Ping Zhu
Journal: Cancer Research (2017)

Abstract Dysregulation of RNA splicing can cause various forms of cancer and neuromuscular disorders. Thus, developing compounds with splicing-modulating activity represents a promising therapeutic approach for these diseases. Natural products such as pladienolide, herboxidiene, and spliceostatin have been identified as potent splicing modulators that bind SF3B1, a member of the SF3b subcomplex that assembles into the U2 snRNP. Using integrated chemogenomic, structural and biochemical approaches, we show that PHF5A, another core component of the SF3b complex, is also targeted by these modulators. Whole exome sequencing of E7107 (pladienolide analogue) and herboxidiene resistant clones identified common mutations in either PHF5A-Y36, SF3B1-K1071, SF3B1-R1074, or SF3B1-V1078, which confers resistance to these modulators as assessed by splicing modulation and cell growth inhibition, suggesting a common site of interaction for these splicing modulators. We determine the crystal structure of human PHF5A and find that Y36 is located on the surface in a region of high sequence conservation. Analysis of the cryo-EM spliceosome Bact complex from yeast shows that these mutations cluster in a well-defined pocket surrounding the branch point adenosine suggesting a possible competitive mode of action for these modulators. Whole-transcriptome RNA-seq analysis reveals that PHF5A Y36C alters the profile of splicing modulators from inducing intron-retention events to exon-skipping events. Furthermore, the differential in GC content between adjacent introns and exons correlates with the relative intron strength, making some splicing events more susceptible to modulation. Collectively, we propose that PHF5A-SF3B1 is a central node for binding to these small-molecule splicing modulators offering novel approaches to modulate specific splicing events. Citation Format: Teng Teng, Jennifer Tsai, Xiaoling Puyang, Michael Seiler, Shouyong Peng, Daniel Aird, Silvia Buonamici, Benjamin Caleb, Betty Chan, Laura Corson, Jacob Feala, Peter Fekkes, Craig Karr, Manav Korpal, Yoshiharu Mizui, Eunice Park, James Palacino, Peter Smith, Vanitha Subramanian, Jeremy Wu, Lihua Yu, Agustin Chicas, Markus Warmuth, Nicholas Larsen, Ping Zhu. A chemogenomic approach reveals the action of splicing modulators at the branch point adenosine binding pocket defined by the PHF5A/SF3b complex [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 126. doi:10.1158/1538-7445.AM2017-126
Abstract 432: xCT inhibition disrupts redox homeostasis in CD44v-expressing tumor cells showing glutaminolytic metabolism in head and neck squamous cell carcinoma
Authors: Shogo Okazaki, Kenji Tsuchihashi, Oltea Sampetrean, Hideyuki Saya, Osamu Nagano
Journal: Cancer Research (2017)

Abstract Metabolic changes favoring aerobic glycolysis and glutaminolysis may influence the sensitivity of tumor cells to anticancer drugs. We previously showed that sulfasalazine, an inhibitor of xCT-dependent cystine transport, selectively induces oxidative damage in undifferentiated tumor cells that express CD44 variant (CD44v) at a high level, without affecting CD44v-negative differentiated tumor cells, in head and neck squamous cell carcinoma (HNSCC). However, whether metabolic changes contribute to the xCT dependency of CD44v-expressing HNSCC cells has remained unknown. Here we show that CD44v-expressing HNSCC cells manifest a highly glutaminolytic phenotype and constitutively generate reactive oxygen species through glutamine metabolism pathway, and that xCT plays a key role in maintaining redox homeostasis in these cells. Inhibition of xCT suppressed the consumption of glutamine without affecting that of glucose in these cells, indicating that CD44v-expressing HNSCC cells also rely on xCT for maintenance of glutaminolysis. Furthermore, administration of sulfasalazine, but not that of the anticancer drug cisplatin, selectively depleted CD44v-expressing undifferentiated tumor cells positive for the glutamine transporter ASCT2 in human HNSCC tumors formed in nude mice. Targeting of xCT is thus a potential therapeutic approach for ASCT2-expressing HNSCC tumors in which cellular metabolism is shifted toward enhanced glutaminolysis. Citation Format: Shogo Okazaki, Kenji Tsuchihashi, Oltea Sampetrean, Hideyuki Saya, Osamu Nagano. xCT inhibition disrupts redox homeostasis in CD44v-expressing tumor cells showing glutaminolytic metabolism in head and neck squamous cell carcinoma [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 432. doi:10.1158/1538-7445.AM2017-432
Abstract 3032: Direct regulation of alternative splicing by Smad3 through PCBP1 is essential to the tumor-promoting role of transforming growth factor beta1
Authors: Veenu Tripathi, Katherine M. Sixt, Xuan Xu, Ying E. Zhang
Journal: Cancer Research (2017)

Abstract In advanced stages of cancers, TGF- β promotes tumor progression in conjunction with inputs from receptor tyrosine kinase pathways. However, the mechanisms that underpin the signaling cooperation and convert TGF- β from a potent growth inhibitor to a tumor promoter are not fully understood. In this work we report that TGF- β directly regulates alternative splicing of cancer stem cell marker CD44 through a phosphorylated T179 of SMAD3-mediated interaction with RNA-binding protein PCBP1. We show that TGF- β and EGF respectively induce SMAD3 and PCBP1 to colocalize in SC35 positive nuclear speckles, and the two proteins interact in the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly in favor of expressing the mesenchymal isoform CD44s over the epithelial isoform CD44E. We further show that the SMAD3-mediated alternative splicing is essential to the tumor-promoting role of TGF- β and has a global influence on protein products of genes instrumental to epithelial to mesenchymal transition and metastasis. Citation Format: Veenu Tripathi, Katherine M. Sixt, Xuan Xu, Ying E. Zhang. Direct regulation of alternative splicing by Smad3 through PCBP1 is essential to the tumor-promoting role of transforming growth factor beta1 [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 3032. doi:10.1158/1538-7445.AM2017-3032