bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5513: Notch directly represses transcription by recruitment of PRC2 to the ternary complex
Authors: Han Xiaoqing , Ranganathan Prathibha , Capobianco Anthony 
Published: July 2017

Abstract
It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. In this study, we report that the Notch ternary complex can also serve to direct the formation of a repressor complex to terminate genes expression of select target genes. Herein we demonstrate that p19Arf and Klf4 are transcriptionally repressed directly by Notch. Data indicate that Notch recruits PRC2 and Lsd1 to these promoters, which leads to changes in the state of the epigenetic landscape and repression of transcription. The demethylase activity of Lsd1 is a pre-requisite for Notch-mediate transcriptional repression. Furthermore, we identified a stable Notch transcriptional repressor complex containing Lsd1, PRC2 and the Notch ternary complex. This study demonstrates proof of concept for a novel function of Notch and provides further insight into the mechanisms of Notch mediated tumorigenesis. This finding provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response.
Note: This abstract was not presented at the meeting.
Citation Format: Xiaoqing Han, Prathibha Ranganathan, Anthony Capobianco. Notch directly represses transcription by recruitment of PRC2 to the ternary 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 5513. doi:10.1158/1538-7445.AM2017-5513
Abstract 5515: Dicer suppresses cytoskeleton remodeling and tumorigenesis of colorectal epithelium by miR-324-5p mediated suppression of HMGXB3 and WASF-2
Authors: Sun Lina , Li Jianming 
Published: July 2017

Abstract
Emerging evidence indicates that microRNAs, a class of small and well-conserved noncoding RNAs, participate in many physiological and pathological processes. RNase III endonuclease DICER is one of the key enzymes for microRNA (miRNA) biogenesis. However, the role of Dicer and its downstream miRNAs in colorectal cancer (CRC) remain largely unclear. Here, we found that Dicer was downregulated in tumour samples of CRC patients at both mRNA and protein levels. Importantly, more tumours were developed in mice with intestinal epithelial cells specific deletion of Dicer (Dicerloxp/+&VillinCre mice) after azoxymethane (AOM) and dextran sulfate sodium (DSS) administration. Interestingly, deletion of Dicer in intestinal epithelial cells led to severe chronic inflammation and cytoskeleton remodeling of intestinal epithelium layer in mice with or without DSS administration. Microarray analysis of 3 paired Dicer deletion CRC cell lines (RKO-WT/RKO-DICER-/-, HCT116-WT/ HCT116-DICER-/- and DLD-WT/DLD-DICER-/-) showed that miR-324-5p was one of the most significant decreased miRNAs. In the intestinal epithelium of Dicerloxp/loxp&VillinCre mice, miR-324-5p was also found to be markedly downregulated. Mechanistically, miR-324-5p directly bound to the 3'untranslated regions (3'UTRs) of HMGXB3 and WASF-2, two key proteins participated in cytoskeleton remodeling, to suppress their expression. Intraperitoneal injection of miR-324-5p AgomiR curtailed chronic inflammation and cytoskeleton remodeling of colorectal epithelium and restored intestinal barrier function in Dicerloxp/+&VillinCre mice induced by DSS. Therefore, our study reveals a key role of a DICER/miR-324-5p/HMGXB3/WASF-2 axis in cytoskeleton remodeling and maintaining integrity of intestinal barriers and as such alludes to the possibility of screening for small-molecule compounds that boost Dicer activity as a potential strategy in the treatment of colorectal cancer.
Citation Format: Lina Sun, Jianming Li. Dicer suppresses cytoskeleton remodeling and tumorigenesis of colorectal epithelium by miR-324-5p mediated suppression of HMGXB3 and WASF-2 [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 5515. doi:10.1158/1538-7445.AM2017-5515
Abstract 5516: Regulation of TFPI-2 in the progression of ovarian cancer
Authors: Fry Jacqueline , Kato Sumie , Abarzua Lorena , Gonzalez Pamela , Ramirez Carolina , Cumsille Elisa , Bravo Erasmo , Correa Raimundo , Leiva Juan E. , Paredes Cesar , Roa Juan C. , Ibañez Carolina , Cuello Mauricio , Owen Gareth I. , Bravo Maria L. 
Published: July 2017

Abstract
Ovarian cancer metastasis occurs when malignant cells migrate from the primary tumor into the ascitic fluid and form a secondary tumor in the peritoneal cavity. The cells responsible for this process, Metastases Initiating Cells (MICs), suffer a series of changes in protein expression, with increased Epithelial Mesenquimal Transition and stem cell markers having been reported. Tissue Factor Pathway Inibitor-2 (TFPI-2) is a serine proteinase inhibitor and potential tumor suppressor gene, whose reduction is correlated with more metastases and poor prognosis. As the exact stage of TFPI-2 loss is still unknown, the purpose of our study was to determine TFPI-2 during ovarian cancer progression. Protein and RNA levels were assessed in primary tumor and metastatic tissue from papillary serous carcinoma by immunohistochemistry and qPCR, respectively. TFPI-2 RNA and protein levels were analyzed in cancer cell lines and primary cultured cancer cells isolated from ascitic fluid of advanced ovarian cancer patients and in cancer spheres derived from these cultures. Epigenetic changes of 3 CpG were analized by bisulfite and pirosequencing technique in ovarian cancer cell lines and in cancer spheres derived from these cultures. We report that significantly decreased TFPI-2 protein levels in metastatic tissue compared to the primary tumor, a result confirmed in matched primary and metastatic lesions from the same ovarian cancer patients. Furthermore, cancer spheres (representing potential MICs) displayed significantly lower levels of TFPI-2 than corresponding cell line and some primary cultured cancer cells. The cancer spheres showed a modest increase in methylation percentage in three specific CpG sites within the TFPI-2 promoter. Our results suggest that TFPI-2 loss plays a role in the cancer cell escape from the primary tumor. Future studies will determine the mechanism and the biological consequences of the progressive loss of TFPI-2 in cancer. Funding: FONDECYT 11140657, 1160800, 1140970, 3140335, 3150028, CORFO L2 13IDL2-18608, IMII-P09/016-F, CONICYT-FONDAP 15130011, BMRC 13CTI21526-P6
Citation Format: Jacqueline Fry, Sumie Kato, Lorena Abarzua, Pamela Gonzalez, Carolina Ramirez, Elisa Cumsille, Erasmo Bravo, Raimundo Correa, Juan E. Leiva, Cesar Paredes, Juan C. Roa, Carolina Ibañez, Mauricio Cuello, Gareth I. Owen, Maria L. Bravo. Regulation of TFPI-2 in the progression of ovarian 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 5516. doi:10.1158/1538-7445.AM2017-5516
Abstract 5517: Antitumor effect of LRIG1, negative regulator of ErbB, in lung cancer harboring mutant-EGFR
Authors: Torigoe Hidejiro , Toyooka Shinichi , Sakaguchi Masakiyo , Shien Kazuhiko , Yamamoto Hiromasa , Soh Junichi , Asano Hiroaki , Tomida Shuta , Tsukuda Kazunori , Miyoshi Shinichiro 
Published: July 2017

Abstract
Introduction: EGFR is a member of the ErbB family of tyrosine kinase receptors (RTKs) and plays important roles in the pathogenesis of certain human cancers. In non-small cell lung cancer (NSCLC), mutations in EGFR gene are commonly known as oncogenic driver mutation and targeted for treatment. Leucine rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell surface protein and known as a negative regulator of ErbB family. In brain tumor, LRIG1 was reported to downregulate not only wild-type EGFR, but also EGFRvIII, mutant-type EGFR. But there has been no report about the relationship between LRIG1 and EGFR mutation in the kinase domain frequently found in lung cancer. In this study, we investigate the role of LRIG in EGFR mutant lung cancer from the view point of its effect on signal transduction and cell proliferation and invasion.
Method: We examined the LRIG1 expression levels in lung cancer cell lines and the surgically resected primary lung cancer tissues by quantitative PCR assay. We made stable clone of EGFR-mutant cell line (HCC827; exon19del E746-A750) overexpressing GFP tagged LRIG1, and compared with stable clone overexpressing GFP alone.
Results: The LRIG1 expression levels in lung cancer cell lines and the surgically resected primary lung cancer tissues were much lower than that in normal bronchial epithelial cells and their normal tissues, respectively. The introduction of LRIG1 decreased EGFR expression and their phosphorylation in EGFR-mutant cell line. LRIG1 strongly suppressed cell proliferation, invasion and migration of EGFR-mutant cell line. In addition, a phospho-RTK array revealed that LRIG1 also downregulated the other RTKs, such as HER2, HER3, MET, and IGF-1R.
Conclusion: Our findings demonstrates that LRIG1 decreases the expression and phosphorylation of mutant-EGFR protein and has strong anti-tumor effect in lung cancer harboring EGFR mutation. These findings suggest the importance of LRIG1 related studies to develop a novel strategy for EGFR mutant cancers.
Citation Format: Hidejiro Torigoe, Shinichi Toyooka, Masakiyo Sakaguchi, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi. Antitumor effect of LRIG1, negative regulator of ErbB, in lung cancer harboring mutant-EGFR [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 5517. doi:10.1158/1538-7445.AM2017-5517
Abstract 5519: psiTPTE22-HERV functions as a tumor suppressor in gastric cancer and is associated with disease outcome
Authors: Liang Jessie Qiaoyi , Xu Fei , Zheng Shu , Yu Jun 
Published: July 2017

Abstract
Background and aim: The novel gene psiTPTE22-HERV identified by us previously is a human endogenous retrovirus (HERV)-related gene located adjacent to the gene psiTPTE22. With a high GC content around the promoter region, expression of psiTPTE22-HERV can be regulated epigentically by DNA methylation. We aimed to elucidate the clinical significance of epigenetic alteration and biological function of psiTPTE22-HERV in gastric cancer.
Methods and results: psiTPTE22-HERV was ubiquitously expressed in normal adult tissues including stomach, but was frequently silenced/down-reguated in gastric tumors and cancer cell lines as evidenced by RT-PCR. Bisulfite genomic sequencing results indicated that psiTPTE22-HERV was silenced by promoter DNA methylation, and its expression could be restored by demethylation treatments in gastric cancer cell lines. Ectopic expression of psiTPTE22-HERV significantly suppressed cell viability, clonogenicity and cell cycle progression, induced apoptosis, and inhibited migration and invasion of SGC7901 and MKN45 gastric cancer cells. In contrast, knock-down of psiTPTE22-HERV in the gastric cancer MKN1 cells significantly increased cell growth and migration ability, promoted cell cycle progress and inhibited cell apoptosis. psiTPTE22-HERV significantly suppressed subcutaneous tumorigenicity of SGC7901 cells in nude mice and metastasis (liver implantation) in tail vein injection models. Promoter methylation level of psiTPTE22-HERV was significantly higher in gastric tumors than in adjacent non-tumor tissues as revealed by bisulfite genomic sequencing (P&lt;0.05); methylation levels in both tumors and adjacent non-tumor tissues of gastric cancer patients were significantly higher than in normal stomach tissues (both P&lt;0.001). Multivariate Cox regression analysis demonstrated that promoter methylation of psiTPTE22-HERV in primary gastric tumors was an independent risk factor for poor survival. Kaplan-Meier survival curves showed that high-methylation of psiTPTE22-HERV promoter was significantly associated with shortened survival in gastric cancer patients from two independent cohorts (both P&lt;0.05).
Conclusion: psiTPTE22-HERV functions as a tumor suppressor that is commonly down-regulated by promoter methylation in gastric cancer, which may serve as a prognostic biomarker for gastirc cancer patients.
Citation Format: Jessie Qiaoyi Liang, Fei Xu, Shu Zheng, Jun Yu. psiTPTE22-HERV functions as a tumor suppressor in gastric cancer and is associated with disease outcome [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 5519. doi:10.1158/1538-7445.AM2017-5519
Abstract 5535: Effect of LKB1 activity on the sensitivity to PI3K/mTOR inhibitor in non-small-cell lung cancer
Authors: Shukuya Takehito , Yamada Tadaaki , Koenig Michael J. , Rahman Mohammad A. , Amann Joseph M. , Carbone David P. 
Published: July 2017

Abstract
The serine-threonine liver kinase B1 (LKB1, also called STK11) is a tumor suppressor that functions as master regulator of cell growth, metabolism, survival and polarity. Germline mutation of LKB1 causes Peutz-Jeghers syndrome, which is an autosomal dominant disease characterized by mucocutaneous pigmentation and hamartomatous polyps. In non-small-cell lung cancer (NSCLC), LKB1 is frequently rendered non-functional, either through mutation or down regulation. As a tumor suppressor and a protein whose function is lost, identifying pathways that are activated with LKB1 loss may be the only way to target such tumors. Some previous studies have suggested that inhibition of mTOR, a growth promoting pathway negatively regulated by LKB1, as a potential target in LKB1 mutant NSCLC. In this study, we investigated the effect of LKB1 activity on the sensitivity to a PI3K/mTOR inhibitor using four LKB1 mutant NSCLC cell lines to which LKB1 gene was transduced and one LKB1 wild type NSCLC cell line in which LKB1 gene was knocked out by CRISPR technology. Transduction of LKB1 resulted in significant resistance to a PI3K/mTOR inhibitor in two of the four LKB1 add-back cell lines, while knocking out LKB1 in the LKB1 wild type cell line induced PI3K/mTOR inhibitor sensitivity. The mechanism behind these observed results appears to be through regulation of phosphorylation of AKT. The presence of LKB1 led to a persistent AKT phosphorylation even in the presence of the PI3K/mTOR inhibitor, both in add back cell and wild type cells. Our data suggest that the identification of LKB1 activity may be a promising biomarker for the sensitivity to PI3K/mTOR inhibition. Further investigation into the mechanism of LKB1 loss and increased sensitivity to inhibition of the PI3K and mTOR pathways is warranted.
Citation Format: Takehito Shukuya, Tadaaki Yamada, Michael J. Koenig, Mohammad A. Rahman, Joseph M. Amann, David P. Carbone. Effect of LKB1 activity on the sensitivity to PI3K/mTOR inhibitor in non-small-cell 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 5535. doi:10.1158/1538-7445.AM2017-5535
Abstract 5536: The metastasis suppressor NME1 regulates stemness in melanoma
Authors: Wang Ying , Kaetzel David M. 
Published: July 2017

Abstract
Melanoma is a lethal skin cancer that is highly resistant to therapy and prone to metastasize to distant organs. The quiescence melanoma stem cells are believed to account for the resistance to therapies. Traditional chemotherapies designed to target fast-proliferative tumor cells tend to miss quiescent stem cells. The escaped quiescent stem cells may accumulate oncogenic mutation from common mutagenic sources and finally lead to tumor relapse. NME1 is a metastasis suppressor gene that inhibits the metastatic potential in melanoma and other cancers. In this study, we focus on the role of NME1 in the regulation of stemness and quiescence of melanoma stem cells. We find that the genesis and growth of stem cell spheroids derived from melanoma cell lines are abrogated after knockdown of NME1. We also find that the mRNA level of several melanoma stem cell markers are elevated when we knockdown NME1. These results suggest that NME1 regulates the survival and stemness of melanoma stem cells. In addition, we demonstrate that melanoma stem cells are heterogeneous in NME1 expression. Specifically, the NME1 expression is markedly elevated in a highly proliferative subpopulation in the spheroids that express the stem cell markers OCT4, SOX2 and SOX10. Conversely, we observe another subpopulation of these spheroids that exhibits low NME1 expression and is non-proliferative. We hypothesize that this subpopulation consists quiescent melanoma stem cells that are more resistance to therapies, and that their quiescent status is controlled by the level of NME1. We are now employing CRISPR technology to separately study potentials in tumorigenesis, metastasis, and therapy-resistance of the stem cell subpopulations.
Citation Format: Ying Wang, David M. Kaetzel. The metastasis suppressor NME1 regulates stemness in melanoma [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 5536. doi:10.1158/1538-7445.AM2017-5536
Abstract 5537: Loss of ITM2A, a novel tumor suppressor of ovarian cancer through G2/M cell cycle arrest, is a poor prognostic factor of epithelial ovarian cancer
Authors: Kim So Young , Lee Eun-Ju , Cho Min Ji , Rhee Hyemin 
Published: July 2017

Abstract
Integral membrane protein 2A (ITM2A) is a type 2 transmembrane protein of unknown function. The aim of this study was to investigate its expression pattern, clinical significance, and biological function in epithelial ovarian cancer. ITM2A expression in 35 normal, 20 adenoma, 11 borderline and 90 cancerous ovarian tissues was measured by immunohistochemistry. Clinicopathological parameters were obtained from medical records. Survival data was analyzed using Kaplan-Meier estimates and multivariate analysis using the Cox-regression method. Anti-tumor activities of ITM2A were explored by cell proliferation and colony formation assays, flow cytometry, Western blots and animal studies using ovarian cancer cell lines. Chemoresponsiveness was evaluated by measuring IC50 and confirmed by animal studies using an intraperitoneal orthotropic model. ITM2A was significantly downregulated in invasive carcinomas compared to normal, adenoma and borderline tumor tissues. ITM2A loss occurred in 45.6% (41 of 90) of invasive carcinomas and was significantly associated with FIGO stage, type II tumors, suboptimal debulking operation, recurrence and chemoresistance. ITM2A loss and higher FIGO stage were independent factors for poor prognosis. Expression of ITM2A inhibited growth and induced G2/M cell cycle arrest by attenuating cdc2, cyclin B1, cdc25c and p-cdc2 (Thr 161). In vitro and in vivo experiments showed that ITM2A expression significantly reduced the paclitaxel and carboplatin IC50 and tumor mass after paclitaxel treatment. ITM2A is a new biomarker of poor prognosis in ovarian cancer. It is a novel tumor suppressor that induces cell cycle arrest, acts as a chemosensitizer, and has therapeutic potential for ovarian cancer.
Citation Format: So Young Kim, Eun-Ju Lee, Min Ji Cho, Hyemin Rhee. Loss of ITM2A, a novel tumor suppressor of ovarian cancer through G2/M cell cycle arrest, is a poor prognostic factor of epithelial ovarian 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 5537. doi:10.1158/1538-7445.AM2017-5537
Abstract 5556: Widespread protein interactome network rewiring in human cancer
Authors: Yi Song , Sahni Nidhi 
Published: July 2017

Abstract
In the past decade, genome and exome sequencing projects have identified thousands of genetic variants in patients across a large number of cancer types. However, the explosion of genomic information has left many fundamental questions regarding genotype-phenotype relationships unresolved. One critical challenge is to distinguish causal disease mutations from non-pathogenic polymorphisms. Even when causal mutations are identified, the functional consequence of such mutations is often elusive. Classical “one gene, one function, one disease” models can not reconcile with the complexity that different mutations of the same gene often lead to different phenotypes. The extent to which network perturbations are involved in disease malfunction and how distinct interaction perturbation patterns can distinguish cancer mutations are largely unknown. Here we report a systematic approach to investigate genetic variant-specific effects on molecular interactions at large scale across diverse human cancers. Remarkably, in comparison to non-disease polymorphisms, disease mutations are more likely to associate with interaction perturbations. A large fraction of missense disease mutations are found to cause protein interaction alterations. While some result in loss of all their interactions, many exhibit selective elimination of specific interactions (“edgetic”). Different mutations of the same gene give rise to different interaction profiles, accounting for distinct disease outcomes. Edgetic mutations perturb interactions through disrupting specific interaction interfaces, and the perturbed partners are more likely expressed in relevant disease tissue. Together, our approach is insightful in prioritizing disease-causing variants, and uncovering patient mutation-specific disease mechanisms at a base-pair resolution, a critical step towards personalized precision medicine. Furthermore, our results suggest distinct interaction perturbations as a widespread mechanism underlying genetic heterogeneity, providing a fundamental link between genotype and phenotype in cancer.
Citation Format: Song Yi, Nidhi Sahni. Widespread protein interactome network rewiring in human 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 5556. doi:10.1158/1538-7445.AM2017-5556