bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2493: Identification of the mutant p53-PARP-MCM chromatin axis as a triple negative breast cancer replication stress target
Authors: Qiu Wei-Gang , Polotskaia Alla , Xiao Gu , Di Lia , Zhao Yuhan , Hu Wenwei , Philip John , Hendrickson Ronald , Bargonetti Jill 
Published: July 2017

Abstract
Approximately 15% of all breast cancer is triple-negative and of these about 80% are found to have mutations in the gene for the tumor suppressor p53 (TP53). Many TP53 mutations encode gain-of-function oncogenic mutant p53 (GOF mtp53) protein. We used inducible knockdown of endogenous GOF mtp53 in MDA-MB-468 cells in conjunction with stable isotope labeling with amino acids in cell culture (SILAC) and subcellular fractionation. We sequenced over 70,000 total peptides for chromatin and cytoplasmic reciprocal data sets and were able to identify 3,010 unique cytoplasmic fraction proteins and 3,403 unique chromatin fraction proteins. We found that the heterohexomeric minichromosome maintenance (MCM) complex (MCM 2-7) along with PARP are high mtp53-chromatin associated pathways. When we depleted R273H mtp53 we found a large reduction of the amount of MCM complex and PARP proteins on the chromatin. Furthermore a direct mtp53-MCM2 interaction was detected. Overexpressed mtp53, but not wild type p53, showed a protein-protein interaction with MCM2 and MCM4. We treated cells with the PARP inhibitor talazoparib and the alkylating agent temozolomide and detected synergistic activation of apoptosis only in the presence of functional MCM2-7 and mtp53. The mtp53-PARP-MCM axis has potential use as a therapeutic and diagnostic target.
Citation Format: Wei-Gang Qiu, Alla Polotskaia, Gu Xiao, Lia Di, Yuhan Zhao, Wenwei Hu, John Philip, Ronald Hendrickson, Jill Bargonetti. Identification of the mutant p53-PARP-MCM chromatin axis as a triple negative breast cancer replication stress target [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 2493. doi:10.1158/1538-7445.AM2017-2493
Abstract 2513: Multi-omics-based approach to colorectal cancer metabolism
Authors: Satoh Kiyotoshi , Soga Tomoyoshi 
Published: July 2017

Abstract
Cancer cells exhibit many metabolic alterations to acquire energy and cellular components required for their proliferation and thus, cancer specific metabolic pathways are attractive targets for cancer therapy. However, the regulation mechanisms underlying metabolic reprogramming are poorly understood. Here, we performed multi-omics-based analyses of paired normal and tumor tissues from patients with colorectal cancer (CRC) to understand the regulation mechanisms of metabolism in colorectal cancer. First, we carried out capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolome profiling of tumor and normal tissue obtained from 275 patients with CRC. S-adenosylmethionine (SAM), a principal methyl group donor produced by one-carbon metabolism, was the most increased metabolite in tumor tissue. Glucose was the second most decreased metabolite in tumor tissue, whereas lactate was accumulated, indicating activation of glycolysis, commonly known as the Warburg effect. Every amino acid except glutamine, the starting metabolite in glutaminolysis, was significantly accumulated in tumor tissue. Interestingly, most of the changes in metabolite levels were occurred in the adenoma stage. In addition, next-generation and Sanger sequencing analyses of genomic DNA obtained from tumor tissue revealed that metabolic alterations occurred independently of mutations in oncogenes and tumor suppressor genes, such as KRAS, APC, and TP53. Furthermore, DNA microarray analysis of paired normal and tumor tissues from CRC patients demonstrated that expression profiles of many metabolic genes were also altered at the adenoma stage. Most of genes regulating purine/pyrimidine synthesis, one-carbon metabolism and fatty acid synthesis were highly expressed, whereas those in fatty acid oxidation were down-regulated in tumor tissue. We will discuss the raised questions, which molecules contribute to the regulation of metabolic reprogramming of colorectal cancer metabolism.
Citation Format: Kiyotoshi Satoh, Tomoyoshi Soga. Multi-omics-based approach to colorectal cancer metabolism [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 2513. doi:10.1158/1538-7445.AM2017-2513
Abstract 2519: Analysis of gene expression patterns and metabolomics correlated to obesity, diabetes, and outcomes in patients with epithelial ovarian cancer
Authors: Montgomery Allison M. , Londono Angelina I. , Craig Eric R. , Tawfik Cindy , Smith Haller J. , Leath Charles A. , Katre Ashwini A. , Cooper Sara J. , Arend Rebecca C. 
Published: July 2017

Abstract
Objective: Diabetes and obesity have been associated with a poor prognosis in ovarian cancer (OVCA); the exact mechanism has yet to be determined. Data suggests that obesity diminishes normal immunological response and better prognoses in non-obese patients may be attributable to an intact immune response. The objective of this study was to analyze the correlation between gene expression pattern/metabolomics and obesity/diabetes in OVCA patients..
Methods: Following IRB approval, UAB patients with suspected OVCA undergoing surgery were consented. Tissue was collected during cytoreduction and 35 samples were analyzed using RNAseq technology and mass spectrometry-based metabolomics. DESeq2 was used for RNAseq analysis to identify gene expression differences between diabetics and non-diabetics stratified by BMI: obese (BMI ≥30) and non-obese (BMI &lt;30). Gene set enrichment analysis was conducted to determine whether there was an over-representation of immune pathways among altered genes. Profiles were normalized in the analysis of the metabolite profiles using ChromaTOF.
Results: 76 genes (p-value &lt;0.05) were differentially expressed in the tumor samples from patients with BMI ≥30 to those &lt;30. These genes were highly enriched for immune-related genes, including 34 immunoglobulin genes, and complement activation. The list of identified genes also included 3 HLA genes (HLA-G(down), HLA-H(up) and HLA-DMA(down). Furthermore, when analyzing tumor from diabetics (n=7), there were 18 genes differentially expressed compared to controls. These genes are not statistically enriched for any functional class. Additionally, genes associated with response to platinum-based therapy, differentiating patients with BMI≥30 v. &lt;30 were analyzed. No genes met genome-wide significance; however, there were 14 genes with a genome-wide p-value&lt;0.1. When diabetes status as a covariate was controlled for, this number was reduced to 9.
Conclusion: By evaluating the transcriptomic profiles generated through RNAseq analysis, a significant number of differences in RNA expression were identified in comparing obese to non-obese OVCA patients. Due to the small sample size, no genes were identied as being associated with the presence or absence of diabetes.
Citation Format: Allison M. Montgomery, Angelina I. Londono, Eric R. Craig, Cindy Tawfik, Haller J. Smith, Charles A. Leath, Ashwini A. Katre, Sara J. Cooper, Rebecca C. Arend. Analysis of gene expression patterns and metabolomics correlated to obesity, diabetes, and outcomes in patients with 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 2519. doi:10.1158/1538-7445.AM2017-2519
Abstract 2535: MicroRNA-518c-5p promotes the metastasis of oral cancer
Authors: Kinouchi Makoto , Uchida Daisuke , Kuribayashi Nobuyuki , Komiyama Yuske , Tsuchida Shuji , Kawamata Hitoshi 
Published: July 2017

Abstract
We have demonstrated that CXCR4 system is involved in the metastatic process of oral cancer. Recently, we identified the miR-518c-5p as a downstream target of the CXCR4 system. In this study, we examined the function of miR-518c-5p on the metastasis of oral cancer. We transfected miR-518c expression vector into oral cancer cells, B88 and CAL27, and isolated stable transfectants, B88-518c and CAL27-518c, respectively. The growth and migration of both cells were significantly enhanced in compared with those of mock cells. LNA-based miR-518c-5p inhibitor significantly impaired the enhanced cell growth and migration of these cells, indicating that these phenomena were dependent on the expression of miR-518c-5p, not on that of miR-518c-3p. Next, we examined the function of miR-518c-5p in vivo. miR-518c or mock transfectants were inoculated into the masseter muscle or the blood vessels of nude mice. Tumor volume, lymph nodes metastasis, and lung metastasis were significantly increased in the mice inoculated with miR-518c transfectants. Furthermore, we examined the mRNA expression induced by miR-518c-5p using B88 cells and B88-518c cells by cDNA microarray analysis. Consequently, some of the genes involved in the cell growth and metastasis were upregulated in the B88-518c cells.
These results indicate that CXCR4 system regulates the metastases of oral cancer via induction of miR-518c-5p.
Citation Format: Makoto Kinouchi, Daisuke Uchida, Nobuyuki Kuribayashi, Yuske Komiyama, Shuji Tsuchida, Hitoshi Kawamata. MicroRNA-518c-5p promotes the metastasis of oral 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 2535. doi:10.1158/1538-7445.AM2017-2535
Abstract 2543: The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma stem cells
Authors: Jiang Wei , Brodie Shlomit , Cazacu Simona , Xiang Cunli , Poisson Laila , Kalkanis Steve , Ginsberg Doron , Brodie Chaya 
Published: July 2017

Abstract
Despite advances in novel therapeutic approaches for the treatment of glioblastoma (GBM), the median survival of 12-14 months has not changed significantly. Therefore, there is an imperative need to identify molecular mechanisms that play a role in patient survival. Here, we analyzed the expression and functions of a novel lncRNA, TALNEC2 that was identified using RNA seq of E2F1-regulated lncRNAs. TALNEC2 was localized to the cytosol and its expression was E2F1-regulated and cell-cycle dependent. TALNEC2 was highly expressed in GBM with poor prognosis, in GBM specimens derived from short-term survivors and in glioma cells and glioma stem cells (GSCs). Silencing of TALNEC2 inhibited cell proliferation and arrested the cells in the G1\S phase of the cell cycle in various cancer cell lines. In addition, silencing of TALNEC2 decreased the self-renewal and mesenchymal transformation of GSCs, increased sensitivity of these cells to radiation and prolonged survival of mice bearing GSC-derived xenografts. Using miRNA array analysis, we identified specific miRNAs that were altered in the silenced cells that were associated with cell-cycle progression, proliferation and mesenchymal transformation. Two of the downregulated miRNAs, miR-21 and miR-191, mediated some of TALNEC2 effects on the stemness and mesenchymal transformation of GSCs. In conclusion, we identified a novel E2F1-regulated lncRNA that is highly expressed in GBM and in tumors from patients of short-term survival. The expression of TALNEC2 is associated with the increased tumorigenic potential of GSCs and their resistance to radiation. We conclude that TALNEC2 is an attractive therapeutic target for the treatment of GBM.
Citation Format: Wei Jiang, Shlomit Brodie, Simona Cazacu, Cunli Xiang, Laila Poisson, Steve Kalkanis, Doron Ginsberg, Chaya Brodie. The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma 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 2543. doi:10.1158/1538-7445.AM2017-2543
Abstract 2544: The lncRNA Meg3 acts as an epigenetic determinant of oncogenic signaling in multiple endocrine neoplasia type 1
Authors: Iyer Sucharitha , Agarwal Sunita 
Published: July 2017

Abstract
Loss of tumor suppressors and gain of oncogenic properties is a hallmark of cancer. But the pathways leading to tumor formation are poorly understood. A good example is the multiple endocrine neoplasia type 1 (MEN1) syndrome, in which patients inherit germline mutations in the MEN1 gene, predisposing to tissue-specific loss of the encoded tumor suppressor protein menin. Consequently, tumors develop in multiple endocrine organs - the pituitary, the parathyroids, and the duodeno-pancreatic tissues, including pancreatic neuroendocrine tumors (PNETs). Insulinomas are the most common type of functioning PNETs that also occur in MEN1 patients. We investigated the molecular pathways associated with insulinomas. We previously showed that menin loss downregulated Maternally Expressed Gene 3 (MEG3), a long non-coding RNA (LncRNA), by eliciting promoter hypermethylation along with the loss of Histone H3 lysine 4 trimethylation (H3K4me3). Gene expression microarray analyses and RT-PCR, of mouse insulinoma MIN6 cells stably transfected with Meg3, showed a 5-fold decrease in the proto-oncogenic signaling receptor c-Met, suggesting a tumor suppressor function for Meg3. We also found MEG3 downregulation with concurrent upregulation of c-MET in PNETs. However, the molecular underpinnings of MEG3 governed c-MET repression remain elusive. To identify the mechanisms by which MEG3 inhibits oncogenic c-MET signaling to suppress tumorigenesis, we examined the effect of various Meg3 isoforms, explored Meg3 association with the epigenetic regulatory machinery, and RNA-DNA triplex formation. We provide direct evidence for the first time that ectopically expressed Meg3 isoforms could attenuate the highly abundant c-Met transcript in MIN6 insulinoma cells. Meg3 also interacted with components of the epigenetic machinery, such as the Polycomb Repressive Complex 2 (PRC2) protein conglomerate, to regulate c-Met RNA expression. Additionally, analyses of triplex forming oligos (TFOs) in MIN6 cells revealed that triple helix formation between Meg3 and dsDNA could potentially disrupt c-Met transcription. Combined, these data offer mechanistic insight into the dysregulation of c-MET repression in PNETs, and support the conclusion that MEG3 acts as an important determinant of oncogenic signaling in MEN1-associated endocrine tumor cells (insulinoma). These findings warrant further investigation into the tumorigenic pathways that may result from the loss of tumor suppressor MEG3 and gain of oncogenic c-MET signaling in other MEN1-associated endocrine tumors.
Citation Format: Sucharitha Iyer, Sunita Agarwal. The lncRNA Meg3 acts as an epigenetic determinant of oncogenic signaling in multiple endocrine neoplasia type 1 [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 2544. doi:10.1158/1538-7445.AM2017-2544
Abstract 2548: Oncogenic function and molecular mechanism of H19 noncoding RNA in colorectal cancer
Authors: Ling Hui , Ohtsuka Masahisa , Ivan Cristina , Pichler Martin , Chen Meng , Slaby Ondrej , Goel Ajay , Radovich Milan , Calin George 
Published: July 2017

Abstract
The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unknown. We analyzed a large panel of cancer-associated lncRNAs in 483 TCGA CRC cases, and identified that H19 correlates most significantly with overall survival and disease-free survival, independent of stage and other clinical parameters. We validated the TCGA findings with two additional CRC cohorts. As one of the “oldest” lncRNAs, diverse activities of H19 including interaction with epigenetic regulators, regulation of microRNAs as competing endogenous RNA (ceRNA), and production of miR-675 as a primary transcript have been reported. However, an unbiased study to clarify the essential mechanisms of H19 is lacking. To decipher the functional involvement of H19 in CRC, we used an integrative approach combining unbiased microarray analysis, experimental validation, and bioinformatic analysis of clinical data. With such approach, we revealed not only previously reported mechanisms such as let-7 and MYC regulation by H19, but also several novel mechanisms that have not been appreciated before. We discovered a mechanism of H19 on regulating RB-E2F signaling and accordingly controlling cell cycle progression. We also identified for the first time that H19 regulates CDK8, an oncogenic driver in CRC pathogenesis, and consequently affects β-catenin activity (Firestein et al., Nature, 2008). We further identified an interaction of H19 with macroH2A, a histone variant reported to repress CDK8 transcription (Kapoor et al., Nature, 2010). Importantly, expression correlation analysis with clinical samples strongly supported the above-identified mechanisms. Combined analysis of H19 with its targets showed strong independent prediction power for CRC survival. These data indicate the clinical relevance of Rb-E2F and CDK8/β-catenin signaling in mediating H19’s oncogenic activity in CRC.
Citation Format: Hui Ling, Masahisa Ohtsuka, Cristina Ivan, Martin Pichler, Meng Chen, Ondrej Slaby, Ajay Goel, Milan Radovich, George Calin. Oncogenic function and molecular mechanism of H19 noncoding RNA in colorectal 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 2548. doi:10.1158/1538-7445.AM2017-2548
Abstract 2549: A long non-coding RNA regulates the androgen receptor and mediates prostate cancer progression
Authors: Pitchiaya Sethuramasundaram , Malik Rohit , Cieslik Marcin , Zhang Yajia , Jiang Xia , Chinnaiyan Arul M. 
Published: July 2017

Abstract
The pervasive expression of long non-coding RNAs (lncRNAs) and their roles in a plethora of cellular processes has revolutionized our understanding of functional genetic elements. Emerging evidence suggest that lncRNAs are promising cancer biomarkers and dysregulation of lncRNAs results in attenuated or accelerated oncogenic phenotypes. In support of these findings, recent reports from the Chinnaiyan lab suggest that lncRNAs can potentially drive and act as independent predictors of aggressive prostate cancer (PCa). Central to PCa progression is the androgen receptor (AR), a nuclear hormone receptor, and the dysregulated transcription program it mediates. Consequently, androgen deprivation therapy (ADT) supplemented with anti-androgens is the initial standard-of-care in treating advanced PCa. Yet, the disease often manifests as a lethal, hormone-refractory castration-resistant prostate cancer (CRPC) after initial ADT and this phenomenon is linked to the resumption of AR activity. Therefore, we sought to identify novel and therapeutically actionable targets of AR that can detect the onset of PCa or stratify PCa variants. To this end, our lab recently characterized the transcriptional landscape of cancer and discovered &gt; 50,000 novel transcripts, a significant fraction of which were tissue- and cancer-specific lncRNAs. Using this updated transcriptome as a reference and performing RNA-seq on PCa cells stimulated with dihydrotestosterone (an androgen), we identified Androgen Receptor regulated lncRNA-1 (ARlnc1) as an important PCa-specific, AR-regulated lncRNA that reciprocally regulates AR. By employing single-molecule fluorescence in situ hybridization (smFISH), we find that ARlnc1 and AR transcripts colocalize within the nucleus of PCa cells and that ARlnc1 promotes transcription of AR. Moreover, we found that ARlnc1 interacts with anti-apoptotic, stress-granule related proteins and regulates PCa cell proliferation in vitro and in mouse xenografts. We have additionally found that anti-sense oligonucleotides (ASOs) that target this lncRNA can reduce tumor growth in xenograft models. Taken together, our data suggests that ARlnc1 and AR reciprocally and positively modulate each other to promote PCa progression and that ARlnc1 may serve as an enhancer RNA that regulates AR transcription. Our data suggests that ARlnc1 can be therapeutically targeted to orthogonally modulate the AR signaling axis for PCa treatment.
Citation Format: Sethuramasundaram Pitchiaya, Rohit Malik, Marcin Cieslik, Yajia Zhang, Xia Jiang, Arul M. Chinnaiyan. A long non-coding RNA regulates the androgen receptor and mediates prostate cancer progression [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 2549. doi:10.1158/1538-7445.AM2017-2549
Abstract 2554: PRR14, a novel regulator of Ras signaling pathway
Authors: Yang Mei , Long Meijun , Shi Xiaoliu , Yuan Zhi-Min , Su Hang 
Published: July 2017

Abstract
PRR14, a component of nuclear lamina, has recently been identified as a novel oncogene in lung cancer. Frequently upregulated in lung cancers, PRR14 promotes tumorigenesis through activating the PI3-kinase/Akt/mTOR signal pathway. The regulatory effect is mediated by direct interaction with GRB2, a docking protein upstream of both PI3K and Ras. Indeed, PRR14 is commonly elevated in many cancer types including lung cancer and breast cancer, but our understanding of the underlying molecular mechanism is still very elusive. Given the complicated interplay between PI3K and Ras signal pathways and their importance in carcinogenesis and optimal treatment, we further explored the effect of PRR14 on Ras activation. We used MCF10A human mammary epithelial cells and its K-RasV12-induced cancerous counterparts to establish isogenic cell lines that express different levels of PRR14. Colony formation and growth curves were monitored simultaneously. Western blot and Ras pull-down activation assay were employed to examine protein level and Ras activity. Cell fractionation was performed to detect protein location. We found that the expression level of PRR14 positively correlated with both Ras protein level and its activity, resulting in consequent changes in cell proliferation and colony formation. Remarkably, elevated PRR14 promoted translocation of Ras from cytoplasm into the cell nucleus and its stabilization. In conclusion, PRR14 sequesters, stabilizes and activates Ras in cell nuclei. When upregulated, PRR14 promotes tumorigenesis, and Ras signaling pathway presents one of the complex underlying mechanisms.
Citation Format: Mei Yang, Meijun Long, Xiaoliu Shi, Zhi-Min Yuan, Hang Su. PRR14, a novel regulator of Ras signaling 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 2554. doi:10.1158/1538-7445.AM2017-2554