bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3425: MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9
Authors: Faltejskova-Vychytilova Petra , Merhautova Jana , Conesa-Zamora Pablo , Slaba Katerina , Machackova Tana , Svoboda Marek , Vecera Marek , Mlcochova Jitka , Juracek Jaroslav , Sana Jiri , Ahmad Parwez , Gablo Natalia , Slaby Ondrej 
Published: July 2017

Abstract
Growing evidence suggests that microRNAs (miRNAs) are involved in the development and progression of colorectal cancer (CRC). In the present study, deregulation and functioning of tumor suppressive miR-215-5p was evaluated in CRC. In total, 448 tumor tissues and 325 paired adjacent healthy tissues have been used for miRNA expression analyses. We proved that miR-215-5p is significantly down-regulated in tumor tissues compared to non-tumor adjacent tissues and its decreased levels correlate with the presence of lymph node metastases, tumor stage, and shorter overall survival in CRC patients. To identify specific cellular processes affected by ectopic expression of miR-215-5p, a series of in vitro experiments have been performed using transient transfection of miR-215-5p mimics into four CRC cell lines. Increased levels of miR-215-5p significantly reduced proliferation, clonogenicity, and migration of CRC cells, lead to cell cycle arrest in G2/M phase and p53-dependent induction of apoptosis. The ability of miR-215-5p to inhibit tumor growth was confirmed in vivo by use of NSG mice model and stable cell line over-expressing miR-215-5p. Finally, we proved epiregulin and HOXB9 to be the direct targets of miR-215-5p by luciferase assay and western blot analyses. Since epiregulin is EGFR ligand and HOXB9, is its transcriptional inducer, we suggest, that the main molecular link between miR-215-5p and CRC cells phenotypes presents the EGFR signaling pathway, which is one of the canonical pathogenic pathways in CRC. This work was supported by Ministry of Health of the Czech Republic, grant nr. 15-33158A, 15-34553A, 15-31627A, 15-34678A, 16-31314A, 16-31765A and by grant of Czech Grant Agency nr. 16-18257S.
Citation Format: Petra Faltejskova-Vychytilova, Jana Merhautova, Pablo Conesa-Zamora, Katerina Slaba, Tana Machackova, Marek Svoboda, Marek Vecera, Jitka Mlcochova, Jaroslav Juracek, Jiri Sana, Parwez Ahmad, Natalia Gablo, Ondrej Slaby. MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9 [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 3425. doi:10.1158/1538-7445.AM2017-3425
Abstract 344: Chondroitin sulfatases regulate Wnt signaling through effects on Shp2, phospho-Erk1,2, c-Myc, and histone methylation of DKK3 in prostate cancer and prostate stem cells
Authors: Tobacman Joanne Kramer , Bhattacharyya Sumit , Feferman Leo 
Published: July 2017

Abstract
The chondroitin sulfatases N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) and N-acetylgalactosamine 6-sulfatase (galactose 6-sulfatase, GALNS) remove the 4-sulfate and 6-sulfate groups of chondroitin sulfates. ARSB acts to remove 4-sulfate groups of chondroitin 4-sulfate (C4S) or dermatan sulfate, and GALNS acts to remove 6-sulfate groups of chondroitin 6-sulfate (C6S) or chondroitin 4,6-disulfate, as well as keratan sulfate. In human prostate cancer tissues, ARSB activity was markedly reduced and GALNS activity increased. By immunohistochemistry of malignant prostate tissue captured by laser microdissection and by assay of human prostate stromal and epithelial cell lines, ARSB was predominant in stromal cells of the extracellular matrix, whereas GALNS predominated in prostate epithelial cells. When ARSB was reduced by silencing in human prostate stem cells or GALNS was increased by overexpression in the stem cells, SHP2 binding to chondroitin 4-sulfate increased, leading to inhibition of phosphatase action and sustained phosphorylation of Erk1,2. Erk activation enabled increase in c-Myc binding to nuclear DNA and increased expression of DNMT 1a, 3a, and 3b. DNMT activation increased following ARSB silencing or GALNS overexpression, and was blocked by ERK inhibition. Increased DNMT activity led to the increased promoter methylation of DKK3, and the subsequent inhibition of nuclear β-catenin nuclear translocation and Wnt signaling. Decline in Wnt signaling was manifested by reduced TCF-LEF nuclear binding, and decline in the mRNA expression of c-Myc and GATA. Since c-Myc activation can lead to increased expression of cell cycle regulators, the changes in chondroitin sulfation mediated by sulfatases can lead to profound effects in cell proliferation. Hence, the modification of sulfatase activity, manifested as increased chondroitin 4-sulfate, provides the platform for an extensive extracellular-intracellular signaling network that can regulate phosphorylation, DNA promoter methylation, and proliferation, and affect development and malignant transformation.
Citation Format: Joanne Kramer Tobacman, Sumit Bhattacharyya, Leo Feferman. Chondroitin sulfatases regulate Wnt signaling through effects on Shp2, phospho-Erk1,2, c-Myc, and histone methylation of DKK3 in prostate cancer and prostate stem 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 344. doi:10.1158/1538-7445.AM2017-344
Abstract 3443: Functional and mechanistic characterization of oncogenic long intervening non-coding RNA Linc-CHD1L-1 in hepatocellular carcinoma
Authors: Tsang Felice H. , Ho Daniel W. , Ng Irene O. , Wong Jack C. 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Due to the asymptomatic nature of HCC, many patients were diagnosed at advance stages and available therapeutic options are very limited. Therefore, a better understanding of the molecular mechanism underlying hepatocarcinogenesis is urgently needed and is crucial for the development of effective treatment. Long intervening non-coding RNAs (lincRNAs) are emerging class of regulatory RNA involved in diverse molecular processes. In this study, we aimed to interrogate lincRNAs expression in HCC and identify novel lincRNAs that contribute to hepatocarcinogenesis. To investigate the global expression profile of lincRNAs in human HCCs, next-generation transcriptome sequencing (RNA-Seq) was performed in 16 pairs of HBV-associated primary HCCs and their corresponding non-tumorous liver tissues. Interestingly, the lincRNA expressions in human HCCs can be unambiguously segregated from their non-tumorous counterparts by unsupervised clustering analysis, suggesting that global lincRNA expression profiles between tumors and non-tumors were remarkably different. From this analysis, we identified linc-CHD1L-1 as the most significant up-regulated lincRNA in HCCs. Clinically, linc-CHD1L-1 was overexpressed in over 80% of HCC patients. Linc-CHD1L-1 expression level in tumors was also shown to be a promising marker for HCC diagnosis. Functionally, knockdown of linc-CHD1L-1 by shRNAs had significantly reduced HCC cell proliferation and cell migration in vitro. Besides, knockdown of linc-CHD1L-1 in HCC cells also substantially abrogated tumorigenicity in subcutaneous tumor model. Mechanistically, the expression of linc-CHD1L-1 was significantly and positively correlated to the expression of its neighboring genes located on the chromosome 1q. Knockout of linc-CHD1L-1 by CRISPR/Cas9 also significantly repressed its neighboring genes expression, suggesting that linc-CHD1L-1 may positively regulate gene expression in a cis-manner. Finally, DAVID pathway analysis performed on linc-CHD1L co-expressed protein coding genes further suggested that linc-CHD1L-1 was significantly co-expressed with genes that are involved in transcription and chromatin modifications. In conclusion, overexpression of linc-CHD1L-1 contributes to hepatocarcinogenesis by promoting HCC cell proliferation and migration through transcriptional and epigenetic mechanisms.
Citation Format: Felice H. Tsang, Daniel W. Ho, Irene O. Ng, Jack C. Wong. Functional and mechanistic characterization of oncogenic long intervening non-coding RNA Linc-CHD1L-1 in hepatocellular 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 3443. doi:10.1158/1538-7445.AM2017-3443
Abstract 3444: LINC00152 regulates cell proliferation via p38 signaling and overexpression predicts poor patient survival in lung cancer
Authors: Feng Shumei , Zhang Jie , Su Wenmei , Bai Shengbin , Xiao Lei , Wang Zhuwen , Lin Jules , Reddy Rishindra , Chang Andrew , Beer David , Chen Guoan 
Published: July 2017

Abstract
Lung cancer is a molecularly-heterogenous disease and the leading cause of cancer mortality. The molecular basis for this heterogeneity remains incompletely understood. In the past few years, long non-coding RNAs (lncRNAs) have emerged as novel mechanisms in mediating cancer biology, although most lncRNAs are still undiscovered. LINC00152 has been identified as highly associated with the tumorigenesis and development in gastric cancer, colon cancer and hepatocellular carcinoma, however, the expression level and its oncogenic roles in lung cancer remains unknown. In the present study, we employed next generation RNA sequencing analysis to reveal dysregulated lncRNAs in lung cancer utilizing datasets of 461 lung adenocarcinomas (LUAD) and 156 normal lung tissues from 3 separate institutions. We found that LINC00152 was 4-fold (p &lt;0.001) overexpressed in lung tumors as compared to their adjacent normal tissues with AUC &gt; 0.8 in these 3 data sets. Patients with high LINC00152 expression have significantly poorer survival than those with low expression (log-rank test, p = 0.003). We verified this diagnostic/prognostic potential in an independent cohort of lung tumor tissues by quantitative RT-PCR. Cell proliferation and colony formation ability were decreased after knockdown of LINC00152 using siRNAs in lung cancer cell lines. The expression of LINC00152 was found primarily in the cytoplasm by qRT-PCR analysis. Trichostatin A treatment indicated that histone acetylation could be one of the mechanisms underlying LINC00152 overexpression in NSCLC and cell-based analyses showed p38 signaling was mainly affected by LINC00152 in vitro. Taken together, our study suggests that LINC00152 is involved in lung tumor growth, may have potential as diagnostic/prognostic marker and that further characterization of this lncRNA as a novel therapeutic target for lung cancer is warranted.
Note: This abstract was not presented at the meeting.
Citation Format: Shumei Feng, Jie Zhang, Wenmei Su, Shengbin Bai, Lei Xiao, Zhuwen Wang, Jules Lin, Rishindra Reddy, Andrew Chang, David Beer, Guoan Chen. LINC00152 regulates cell proliferation via p38 signaling and overexpression predicts poor patient survival in lung 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 3444. doi:10.1158/1538-7445.AM2017-3444
Abstract 3447: Down-regulation of long non-coding RNA MALL-2 is associated with metastasis and poor survival in lung adenocarcinoma
Authors: Dang Ha X. , White Nicole M. , Rozycki Emily B. , Maher Christopher A. 
Published: July 2017

Abstract
Lung adenocarcinoma accounts for ~40% of lung cancers and is among the deadliest cancers worldwide. Patients with metastatic lung adenocarcinoma exhibit poor outcome with the average 5-year survival of ~1%. Long non-coding RNAs (lncRNAs) have recently emerged as having critical roles in tumorigenesis. While a subset of lncRNAs have been shown to promote tumor invasion and metastasis, little is known about the role of lncRNAs in metastatic lung adenocarcinoma. Therefore, we analyzed publicly available microarray and RNA-Seq gene expression datasets that include primary and metastatic tissues. Through this meta-analysis we discovered 98 metastasis associated lncRNAs that were dysregulated in metastatic tumors compared to non-metastatic tumors (MALLs). Notably, only two lncRNAs (MALL-2 and MALL-36) were found to be down-regulated in primary tumors, relative to normal tissue, and even further down-regulated in metastatic tumors relative to primary tumors. Gene set enrichment analysis revealed that MALL-2, the most down-regulated lncRNA in metastasis, was coexpressed with protein-coding genes enriched with biological concepts associated with repressing tumor growth and metastasis. Furthermore, we found that FOXA2, a metastasis repressor gene, was highly coexpressed with MALL-2 in lung cancer. A pan-cancer analysis using ~7,000 TCGA RNA-Seq tumor samples across 20 cancer types revealed that MALL-2 was also down-regulated and coexpressed with FOXA2 in multiple cancers suggesting the conserved regulatory relationship between the two genes. We confirmed that FOXA2 expression was decreased upon knock-down of MALL-2 and silencing MALL-2 resulted in a significant increase in cellular migration in lung adenocarcinoma cell lines. Last, we found that low expression of MALL-2 was consistently associated with poor overall survival across multiple independent lung adenocarcinoma cohorts. Taken together, our integrative analysis has revealed MALL-2 that acts as a repressor of lung adenocarcinoma metastasis by regulating FOXA2 and could serve as a biomarker of lung adenocarcinoma patient outcome.
Citation Format: Ha X. Dang, Nicole M. White, Emily B. Rozycki, Christopher A. Maher. Down-regulation of long non-coding RNA MALL-2 is associated with metastasis and poor survival 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 3447. doi:10.1158/1538-7445.AM2017-3447
Abstract 3449: Genistein inhibits renal cancer progression through long non-coding RNA HOTAIR suppression
Authors: Imai-Sumida Mitsuho , Majid Shahana , Dasgupta Pritha , Kulkarni Priyanka , Saini Sharanjot , Bhagirath Divya , Kato Taku , Maekawa Shigekatsu , Hashimoto Yutaka , Shiina Marisa , Deng Guoren , Shahryari Varahram , Tanaka Yuichiro , Dahiya Rajvir , Yamamura Soichiro 
Published: July 2017

Abstract
Genistein, a soy isoflavone, has been shown to have anticancer effects on various cancers in vitro and in vivo including renal cancer. Long non-coding RNAs (lncRNAs) are differentially expressed in various tissues and have important functions in cellular processes such as cell proliferation, motility and apoptosis in various malignancies. HOX transcript antisense RNA (HOTAIR) is a lncRNA localized in the Homeobox C gene cluster on chromosome 12. HOTAIR interacts with the polycomb repressive complex 2 (PRC2), which enhances H3K27 trimethylation and represses the expression of tumor suppressors. In various cancers, HOTAIR is highly expressed and involved in their progression and metastasis. In this study, we investigated the molecular mechanisms of genistein action through a novel pathway that represses HOTAIR. We found that HOTAIR expression is higher in renal cancer cell lines compared to normal controls. Genistein treatment was found to significantly decrease HOTAIR expression in renal cancer cells (786-O and ACHN cells). Genistein treatment also reduced expression of epithelial-to-mesenchyme transition (EMT)-related proteins (ZEB1, Vimentin and Snail), causing reduced cell migration, invasion, and increased apoptosis. We performed RNA immunoprecipitation assays, and found that genistein inhibits HOTAIR binding to PRC2. One of the other EMT markers, a tight junction protein ZO-1, is upregulated by genistein. We are currently investigating if genistein represses PRC2 recruitment to the ZO-1 promoter by inhibiting binding of HOTAIR to PRC2. Our results indicate that genistein is a potent therapeutic agent for renal cancer.
Citation Format: Mitsuho Imai-Sumida, Shahana Majid, Pritha Dasgupta, Priyanka Kulkarni, Sharanjot Saini, Divya Bhagirath, Taku Kato, Shigekatsu Maekawa, Yutaka Hashimoto, Marisa Shiina, Guoren Deng, Varahram Shahryari, Yuichiro Tanaka, Rajvir Dahiya, Soichiro Yamamura. Genistein inhibits renal cancer progression through long non-coding RNA HOTAIR suppression [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 3449. doi:10.1158/1538-7445.AM2017-3449
Abstract 345: PTEN tumor suppressive effects in glioblastoma are partly mediated by MET downregulation via a p53-miR-34a axis
Authors: Guessous Fadilla , Cruickshanks Nichola A. , Zhang Ying , Schiff David , Sarkaria Jann , Abounader Roger 
Published: July 2017

Abstract
Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. Two common alterations in GBM are loss of the tumor suppressor PTEN and upregulation of the oncogenic receptor tyrosine kinase MET. We uncovered a new connection between PTEN and MET expressions and functions in GBM. We found that PTEN expression in GBM cell lines (U87, U373, A172, LNZ-308) and primary cells (GBM8) inhibits MET expression. We uncovered the molecular basis and functional significance of this connection. Based on our previous work and published literature, PTEN stabilizes p53, p53 induces miR-34a expression, and miR-34a inhibits MET expression. We therefore hypothesized that PTEN inhibits MET by regulating p53 and miR-34a and that the PTEN tumor suppressive effects are partly mediated by MET downregulation. To verify the hypothesis, we first showed that PTEN restoration leads to miR-34a upregulation in GBM cells. We then showed that this latter effect is p53-dependent as p53 knockdown with a specific shRNA partly reversed PTEN induction of miR-34a. We also showed that PTEN-induced downregulation of MET expression can be rescued by inhibition of miR-34a with an anti-miR3a. We therefore established a new molecular cascade that links PTEN, p53, miR-34a and MET in GBM. To determine the functional relevance of this cascade, we assessed the effects of PTEN on GBM cell death and invasion also in the settings of shRNA-mediated knockdown of p53 and anti-miR-mediated inhibition of miR-34a. PTEN strongly induced GBM cell death (measured by Annexin V/7AAD flow cytometry) and inhibited transwell invasion though a collagen IV matrix. The PTEN effects on cell death and invasion were partly reduced by p53 knock-down and miR-34a inhibition. This demonstrates that the tumor suppressive effects of PTEN in GBM are partly mediated by the PTEN/p53/miR-34a/MET cascade. In ongoing experiments, we are investigating the expressions of PTEN, MET, p53 and miR-34a in human GBM tissues to determine if there are potential correlations that are consistent with our above findings. Altogether, this study establishes a new molecular and functional link between PTEN and MET that involves p53 and miR-34a in GBM.
Citation Format: Fadilla Guessous, Nichola A. Cruickshanks, Ying Zhang, David Schiff, Jann Sarkaria, Roger Abounader. PTEN tumor suppressive effects in glioblastoma are partly mediated by MET downregulation via a p53-miR-34a axis [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 345. doi:10.1158/1538-7445.AM2017-345
Abstract 3450: Identification of a novel lncRNA involved in Bcr-Abl mediated cellular transformation
Authors: Chen Jilong , Wang Xuefei 
Published: July 2017

Abstract
Aberrant expression of long noncoding RNAs (lncRNAs) is associated with various human cancers. However, little information is available about functional involvement of lncRNAs in tumorigenesis of chronic myeloid leukemia (CML) induced by Bcr-Abl oncogene. In this study, we performed a comprehensive analysis of lncRNAs in human CML cells using an lncRNA cDNA microarray combined with drug treatment. We identified an lncRNA termed lncRNA-up38 that was critically involved in Bcr-Abl-mediated cellular transformation. We found that expression of lncRNA-up38 was greatly upregulated by inhibiting Bcr-Abl kinase activity in K562 cells and leukemic cells derived from CML patients. Furthermore, our experiments demonstrated that lncRNA-up38 acted as a key regulator of 4EBP1 functioning during Bcr-Abl-mediated cellular transformation. Moreover, silencing lncRNA-up38 promoted leukemic cells survival and enhanced Bcr-Abl-mediated tumorigenesis, whereas forced expression of lncRNA-up38 sensitized leukemic cells to undergo apoptosis and inhibited Bcr-Abl-induced tumorigenesis. Additionally, our experiments have begun to address the mechanism of how lncRNA-up38 is regulated in the leukemic cells and showed that Bcr-Abl repressed lncRNA-up38 expression through c-Myc-dependent signaling. Taken together, these results reveal that Bcr-Abl-mediated cellular transformation is associated with downregulation of tumor-suppressor lncRNA-up38 and suggest a potential strategy for the treatment of Bcr-Abl-positive leukemia.
Note: This abstract was not presented at the meeting.
Citation Format: Jilong Chen, Xuefei Wang. Identification of a novel lncRNA involved in Bcr-Abl mediated cellular transformation [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 3450. doi:10.1158/1538-7445.AM2017-3450
Abstract 3458: Role of zyxin in mitosis and colon cancer
Authors: ZHOU JIULI , Dong Jixin , CHEN YUANHONG , CHEN XINGCHENG , Stauffer Seth , Zeng Yongji 
Published: July 2017

Abstract
Zyxin is a LIM domain protein that is concentrated at sites of cell-cell adhesion, where it is proposed to dock proteins involved in cytoskeletal dynamics and signaling. Recently, Zyxin has been shown to promote LATS degradation and YAP activation in Hippo Pathway. Here, We have identified a novel mechanism for phospho-regulation of Zyxin in mitosis and its biological significance in colon cancer. We found that the mitotic kinase cyclin-dependent kinase 1 (CDK1) phosphorylates Zyxin in vitro and in vivo at serine 281, serine 308 and serine 344 during antimitotic drug-induced G2/M phase arrest and unperturbed mitosis. Moreover, Zyxin mitotic phosphorylation-deficient mutant (Zyxin3A, harboring S281A/S308A/S344A) was sufficient to suppress colon cancer cell proliferation and migration. We further demonstrated that depletion of Zyxin resulted in impaired colon cancer tumorigenesis in vitro and in vivo through inhibiting F-actin cytoskeleton and YAP activity. Importantly, these observations could be fully rescued by re-expression of wild type Zyxin, but not Zyxin-3A mutant. Expression profile analysis revealed CDK8 (cyclin-dependent kinase 8) as a mediator downstream Zyxin/YAP. Inhibition of CDK8 phenocopied knockdown of Zyxin in colon cancer cells. Ectopic expression of CDK8 substantially restored the tumorigenic ability of Zyxin depletion cells in vitro and in vivo. Expression levels of Zyxin and CDK8 are both elevated in colon tumors and are negatively correlated with survival. Together, our findings reveal a novel layer of regulation for Zyxin in mitosis and define the Zyxin-YAP-CDK8 axis as a novel oncogenic regulator in colon cancer.
Citation Format: JIULI ZHOU, Jixin Dong, YUANHONG CHEN, XINGCHENG CHEN, Seth Stauffer, Yongji Zeng. Role of zyxin in mitosis and 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 3458. doi:10.1158/1538-7445.AM2017-3458