bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4409: Cholesterol pathway determines ovarian cancer drug resistance through transcription factor SREBP2
Authors: Karashchuk Galina , Karashchuk Nataliya , Caksa Signe , Smith Tyler S. , Brodsky Alexander S. 
Published: July 2017

Abstract
Ovarian cancer is the most common cause of gynecological cancer death in women in United States. Up to 70% of all ovarian cancer cases are high-grade serous carcinomas with 5-year survival rates less than 30%. Recent studies have suggested the importance of the cholesterol pathway in multiple cancers including gynecological malignancies. Here we demonstrate that genetic or pharmacological disturbance of cholesterol pathway in high-grade serous ovarian carcinoma cell lines results in significant changes in survival rate after drug treatment, and in protein and RNA expression patterns.
SREBP2 is a transcription factor encoded by SREBF2 gene that regulates expression of sterol-regulated genes and thus maintains cholesterol homeostasis. To assess the role of SREBP2 in ovarian cancer we have created a stable OVCAR8 cell line with SREBF2 disrupted using CRISPR technology. This SREBF2-KD line has reduced SREBF2 mRNA and protein expression level that indicates an effective gene knockdown. Activation of SREBF2 is dependent on the cholesterol status of the cell. We observed that expression of the SREBP2 precursor form is significantly reduced in SREBF2-KD line when cells are maintained under low serum conditions. Mutant cells treated with paclitaxel in low, but not high serum or in presence of statin, revealed significantly lower cell viability. SREBF2-KD cells do not survive long-term, high concentrations of paclitaxel, nor do they grow back as efficiently as control cells. RNA expression and proteomic analysis revealed the critical regulators mediating SREBP2 activity in stressed cells. Together, these observations suggest that the cholesterol pathway is critical for ovarian cancer cells not only to resist stresses, such as chemotherapy, but also to return to a high proliferation state upon recurrence. Further studies will provide important targets for developing new drugs for treatment of ovarian cancer.
Citation Format: Galina Karashchuk, Nataliya Karashchuk, Signe Caksa, Tyler S. Smith, Alexander S. Brodsky. Cholesterol pathway determines ovarian cancer drug resistance through transcription factor SREBP2 [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 4409. doi:10.1158/1538-7445.AM2017-4409
Abstract 4413: Targeting glutamine metabolism in MUC1 expressing triple negative breast cancer
Authors: Goode Gennifer D. , Gunda Venugopal , Singh Pankaj 
Published: July 2017

Abstract
Breast cancer, the second leading cause of cancer deaths in women, accounts for nearly 1 in 3 cancer cases diagnosed in the U.S. women. Triple negative breast cancer (TNBC) accounts for approximately 15-25% of all breast cancer cases and has an increased incidence of metastasis, high recurrence within 1-3 years and a high mortality rate. Therefore, identifying factors that facilitate tumor growth and metastasis have the potential to serve as novel molecular targets for breast cancer therapy. Mucin1 (MUC1), a glycoprotein associated with chemoresistance, is aberrantly overexpressed in TNBC and facilitates growth and metastasis of TNBC cells. Recent studies suggest a role for MUC1 in modulating cancer cell metabolism to support tumor growth. In the present study we examined the role that MUC1 plays in TNBC tumor metabolism; thus facilitating tumor growth. Our results indicate that MUC1 expression facilitates glutamine metabolism. A correlation between MUC1 expression, glutamine dependency, and amino-oxyacetate (AOA) sensitivity was established. These alterations can be attributed in part to alterations in the expression of genes regulating glutamine metabolism. Collectively, these findings suggest that MUC1 serves as a metabolic regulator in TNBC, facilitating metabolic reprogramming of glutamine that influences growth of TNBC. Additionally, the findings with AOA’s effectiveness provide evidence for potential therapeutic utility, particularly for MUC1 overexpressing TNBC.
Citation Format: Gennifer D. Goode, Venugopal Gunda, Pankaj Singh. Targeting glutamine metabolism in MUC1 expressing triple negative 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 4413. doi:10.1158/1538-7445.AM2017-4413
Abstract 4416: Studies on role of acyl-CoA cholesterol acyltransferase (ACAT) expression in ovarian/endometrial cancer progression - An invitro study
Authors: Ayyagari Vijayalakshmi N. , Wang Xinjia , Brard Laurent 
Published: July 2017

Abstract
INTRODUCTION: Cancer progression and tumorigenesis have been linked to alterations in cellular metabolic pathways of lipid and cholesterol synthesis in many cancers. Increased levels of cholesterol esters (CE) have been reported in breast cancer, leukemia, glioma and prostate cancer, but not exploited in detail in ovarian and endometrial cancers. Inside cells, excess free cholesterol is esterified by acyl-CoA cholesterol acyltransferase (ACAT) and stored as cholesteryl ester (CE) in lipid droplets (LDs). Cholesteryl ester accumulation may be a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway as observed in pancreatic cancer. In the present study, we focused on the role of ACAT and cholesterol esters in altered cholesterol metabolism in ovarian/endometrial cancer cell lines.
METHODS: We studied the effect of abrogation of cholesterol esterification either by an ACAT-1 inhibitor/shRNA knockdown or via inhibition of PI3K/AKT/mTOR pathways and subsequent effect on ovarian/endometrial cancer cells proliferation, invasion, cell migration and tumorigenesis. The expression of ACAT was studied at the protein and mRNA levels in a panel of ovarian/ endometrial cancer cell lines and also in normal and ovarian cancer clinical samples. ACAT expression was assessed by western blotting, ELISA, quantitative RT-PCR and immunostaining techniques.
RESULTS: Our results reveal an elevated expression of ACAT-1 at both protein and mRNA levels in ovarian and endometrial cancer cell lines as compared to primary cells. Our results also provide preliminary data on involvement of ACAT and cholesterol esters in the progression and metastasis of ovarian cancer.
CONCLUSION: These studies may aid in the development of new biomarkers or treatment targets for ovarian/endometrial cancer.
Citation Format: Vijayalakshmi N. Ayyagari, Xinjia Wang, Laurent Brard. Studies on role of acyl-CoA cholesterol acyltransferase (ACAT) expression in ovarian/endometrial cancer progression - An invitro study [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 4416. doi:10.1158/1538-7445.AM2017-4416
Abstract 4421: IGF2 regulates mitochondrial cell energy phenotype and biogenesis in TNBC cells
Authors: Pagan Maria L. , Radhakrishnan Vinodh Kumar , Leon Daisy De 
Published: July 2017

Abstract
Triple-negative breast cancer (TNBC) is very aggressive, resistant to chemotherapy and more likely to relapse, causing the worst prognosis. African American (AA) women suffer higher incidence and mortality of TNBC due to the expression of high levels of Insulin Growth Factor 2 (IGF2) which promotes tumor progression, metastasis, and chemoresistance. Also, it has been established that functional mitochondria and mitochondrial DNA (mtDNA) are essential for cancer cell growth. Mutations and/or reductions in mtDNA copy number that alter the Oxidative Phosphorylation (OXPHOS) physiology are common features of TNBC. We have demonstrated that mtDNA content is lower in CRL-2335 AA TNBC cell line when compared to the CRL-2335 IGF2 knockout cell line. Thus, we propose that IGF2 regulates the mtDNA content. This study was designed to demonstrate if IGF2 regulates mitochondrial genes to determine the cell energy phenotype. An XFp analyzer was used to study the mitochondrial function in terms of OCR (Oxygen Consumption Rate/Mitochondrial Respiration) and ECAR (Extracellular Acidification Rate/ Glycolysis) in the wild type and IGF2 stable knockout of CRL-2335 AA TNBC cells. Real Time PCR was performed to study the gene expression pattern of IGF2, PGC1α and PGC1β. PGC1α and PGC1β are critical genes in the regulation of the mitochondrial biogenesis, thus, they are important in the cellular metabolic phenotype. Utilizing the Seahorse metabolic system we assessed cell energy phenotype and alterations in terms of mitochondrial respiration rate (OCR) % and Glycolysis (ECAR) %. Our preliminary results showed that the overall OCR and ECAR of the stressed CRL-2335 AA TNBC cells was altered according to the levels of IGF-II expressed. Furthermore, the results demonstrated that there was a metabolic shift in the CRL-2335 AA TNBC cells towards the glycolytic pathway when IGF2 was knockout in comparison to the wild type CRL-2335 cells. Also, IGF2 knockout cells showed higher gene expression rate of PGC1β as compared to the wild type. The above data confirms that IGF2 plays a critical role in determining the cell energy phenotype.
Citation Format: Maria L. Pagan, Vinodh Kumar Radhakrishnan, Daisy De Leon. IGF2 regulates mitochondrial cell energy phenotype and biogenesis in TNBC 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 4421. doi:10.1158/1538-7445.AM2017-4421
Abstract 4425: Analysis of host-Epstein-Barr virus microRNA expression in nasopharyngeal carcinoma
Authors: Su Wen-Hui , Zhang Jia-Hao , Chang Kai-Ping 
Published: July 2017

Abstract
In the tumorigenesis process, miRNAs could act as oncogenes or tumor suppressor genes in the cancer cells by regulating miRNA target genes. Nasopharyngeal carcinoma (NPC) associated Epstein-Barr virus (EBV) can also influence the occurrence of NPC through its miRNAs. In this study, we used the next generation sequencing technology to analysis host-viral miRNA profiles in 24 NPC and 5 adjacent normal tissues. In average, 10.62% of mappable reads mapped to EBV genome in NPC tissue. Most of the small RNAs in NPC tissues which mapped to EBV genome were miRNAs (95.51%), rest of them were EBERs (1.80%) and v-snoRNA1 (2.68%). The percentages of EBV miRNA in total human and EBV mature miRNA reads were ranged from 4% to 51% (average 29.61%). For EBV miRNAs, the expression level of BART10-3p and BART9-3p were the top two in NPC tumors. BART20-5p, BART19-3p and BART21-5p were correlated to tumor stage. On the other hand, there were 11 and 34 human miRNAs differentially up- and down-regulated in NPC tissue, respectively. The present research provides the first evidence obtained through direct sequencing to systematically and comprehensively describe the expression of EBV and human miRNAs in NPC tissue.
Citation Format: Wen-Hui Su, Jia-Hao Zhang, Kai-Ping Chang. Analysis of host-Epstein-Barr virus microRNA expression in nasopharyngeal 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 4425. doi:10.1158/1538-7445.AM2017-4425
Abstract 443: Lymphatic endothelium protects breast cancer cells from death by inducing metabolic adaptations
Authors: Berisa Mirela , Podgrabinska Simona , Nicolay Brandon , Mostoslavsky Raul , Chipuk Jerry , Skobe Mihaela 
Published: July 2017

Abstract
The lymphatic vasculature is an important pathway for breast cancer dissemination, yet it is not understood whether and how the lymphatic vessel microenvironment influences cancer metastasis. We demonstrate that lymphatic endothelial cells (LECs) promote survival of triple-negative breast cancer cells (TNBCs) under stress by improving mitochondrial function and inducing metabolic shift to promote cellular energy production. LECs protected TNBCs from death in vitro induced by the loss of attachment and nutrient deprivation. Cell death was preceded with a sharp increase in reactive oxygen species (ROS), strong up-regulation of Nrf2-mediated oxidative stress response genes and a rapid decline of mitochondrial activity. LECs lowered ROS levels, decreased mitochondrial superoxide formation and enhanced mitochondrial activity in TNBCs. RNAseq transcriptome analysis identified key regulator of mitochondrial metabolism and cellular bioenergetics, peroxisome proliferator-activated receptor gamma coactivator (PPARGC1A/PGC-1α, to be specifically up-regulated in breast cancer cells by LEC-derived factors. Inhibition studies demonstrated that the TNBC survival was dependent on pentose phosphate pathway (PPP) activity. Notably, LECs induced a metabolic shift from glycolysis to fatty-acid oxidation (FAO) and oxidative phosphorylation to maintain ATP and sustain cell viability. These data demonstrate that lymphatic endothelium promotes survival of breast cancer cells by regulating energy production and maintaining redox homeostasis. Our findings suggest that lymphatic endothelium may facilitate metastasis by promoting survival of breast cancer cells within the lymphatic vasculature.
Citation Format: Mirela Berisa, Simona Podgrabinska, Brandon Nicolay, Raul Mostoslavsky, Jerry Chipuk, Mihaela Skobe. Lymphatic endothelium protects breast cancer cells from death by inducing metabolic adaptations [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 443. doi:10.1158/1538-7445.AM2017-443
Abstract 4447: Analysis of small RNA-seq data for differential expression of small noncoding RNAs in human colorectal cancer
Authors: Koduru Srinivas V. , Tiwari Amit K. , Hazard Sprague W. , Mahajan Milind K. , Ravnic Dino J. 
Published: July 2017

Abstract
Background: Cancer is a major cause of deaths worldwide, despite improved healthcare and technologies. Recent advancements in genome sequencing have led to the rapid study of the whole transcriptome and small RNAs with their biological functions. Non-coding RNAs (ncRNAs) play an important role in biological processes that greatly impact biomarker development for diagnosis, prognosis, and therapy. Non-coding RNAs such as microRNAs (miRNA), Piwi-interacting-RNAs (piRNAs), small nuclear/nucleolar RNAs (sn/snoRNAs) have recently been studied to understand their biology and pathology.
Results: In the present study, we used eight matched colorectal patient tissue samples (benign, tumor, and metastasis) small RNA sequencing data remapped for various small RNA annotation. We identified aberrant expression of 13 miRs in tumor and metastasis specimens [tumor vs benign group (19 miRs) and metastasis vs benign group (38 miRs)] of which five were upregulated, and eight were downregulated, during disease progression. We also investigated pathway analysis on abbarent expression of miRNAs, which showed majority of miRs involved in the colon other types of cancers. Further analysis of piRNAs revealed that six piRNAs in tumor vs benign and 24 in metastasis vs benign samples (commonly in both groups, only two piRNAs). Additionally, we examined other types of small RNAs [sn/snoRNAs, mt_rRNA, misc_RNA, nonsense mediated decay (NMD) and rRNA], we identified 15 in tumor vs benign and 104 metastasis vs benign and only four in commonly expressed.
Conclusion: In summary, our results identified multiple sncRNAs during colorectal cancer progression which needs to be further validated and can be used for prognosis, diagnosis, and therapeutic potentials.
Citation Format: Srinivas V. Koduru, Amit K. Tiwari, Sprague W. Hazard, Milind K. Mahajan, Dino J. Ravnic. Analysis of small RNA-seq data for differential expression of small noncoding RNAs in human 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 4447. doi:10.1158/1538-7445.AM2017-4447
Abstract 4466: The key role of Abi1 loss in dysregulating cell-cell adhesion during prostate cancer tumorigenesis
Authors: Das Disharee , Hryniewicz-Jankowska Anita , Hehnly Heidi , Post Dawn , Bratslavsky Gennady , Kotula Leszek 
Published: July 2017

Abstract
Prostate cancer accounts for 20-25% of cancer cases every year and is predicted at over 180,000 new cases in 2016. However, the mechanisms of prostate cancer initiation and castration resistance still remains poorly understood. Our previous research shows mutations and deletions in Abelson interactor 1 (Abi1), an integral part of WAVE complex, in prostate tumor samples. Moreover, WAVE complex levels are inversely correlated to prostate cancer recurrence and castration resistance, outlining their clinical significance. A common phenomenon found early on in most cancers, including prostate cancer, is dysregulated cell-cell adhesion. This points towards a possible tumor suppressor mechanism, since Abi1 and the WAVE complex are in fact the primary regulators of branched actin polymerization via the Arp2/3 complex, and are critical for the formation and maintenance of cell-cell adhesion complexes. Hence, to study Abi1 in prostate cancer, we generated a prostate-specific conditional Abi1 knock-out (KO) mouse. In these mice, we observed evidence of prostatic intraepithelial neoplasia (PIN), a precursor of invasive carcinoma, with changes in proliferation and cell-cell adhesion markers. The goal of this study is to elucidate the mechanism by which the loss of Abi1 leads to the development of PIN in these mice. We are leading this analysis by primary 3D cultures with cells from our Abi1 KO prostates, and 2D cultures with mouse embryonic fibroblasts (MEFs). Loss of Abi1 leads to increase in size of the cultured spheroids, which indicates increased proliferation and dysregulated cell-cell adhesion. Also, adherens junction (AJ) markers E-cadherin and β-catenin levels are lower in western blots and immunostaining, suggesting defects in cell-cell adhesion. In MEFs, we observe loss of membrane localization of AJ proteins in Abi1 KO cells. Loss of Abi1 is often associated with upregulation of Abi2, which may be a contributing factor to the phenotype. To validate our findings in a human system, we have recently developed a CRISPR-mediated KO of Abi1 in the RWPE-1 non-tumor prostate cell line. We will use this KO cell line to determine cell-cell adhesion formation and maintenance in 2D and 3D cultures. In conclusion, loss of Abi1 leads to dysregulation of cell-cell adhesion in prostate epithelial cells, which may be a key mechanism for tumor development and progression in prostate cancer. Supported by NCI R01 CA161018 (LK).
Citation Format: Disharee Das, Anita Hryniewicz-Jankowska, Heidi Hehnly, Dawn Post, Gennady Bratslavsky, Leszek Kotula. The key role of Abi1 loss in dysregulating cell-cell adhesion during prostate cancer tumorigenesis [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 4466. doi:10.1158/1538-7445.AM2017-4466
Abstract 4477: HnRNP Q1 translationally increases the expression of Aurora-A and promotes tumorigenesis in colorectal cancer
Authors: Hung Liang-Yi 
Published: July 2017

Abstract
Abnormally elevated Aurora-A can cause mitotic defects and aneuploidy, which might lead to genomic instability and tumorigenesis. According to the literatures, overexpressed Aurora-A may result from gene amplification, RNA transcriptional activation, or increased protein stability. Our previous study has demonstrated that Aurora-A can be translational upregulated in colorectal cancer. By biotin pull-down assay and in vivo translational assay, we found that Aurora-A mRNA can be translational upregulated by heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, a RNA binding protein. Hn RNP Q1 has been implicated in many posttranscriptional regulatory processes including mRNA splicing, RNA metabolism and translation. In this study, we further clarified the regulatory mechanism of hnRNP Q1 in translational regulating Aurora-A mRNA, as well as investigated the clinical role of hnRNP Q1 in colorectal carcinogenesis. Our results indicated that hnRNP Q1 can bind to the Aurora-A mRNA 5’-untranslated region (5’-UTR). Ribosomal protein S6-IP assay further indicated that hnRNP Q1 can enhance the translational efficacy of Aurora-A mRNA. Ribosomal profiling assay further confirmed the translational regulation of Aurora-A mRNA by hnRNP Q1. Overexpression of hnRNP Q1 promotes cell proliferation and tumor growth. The expression level of hnRNP Q1 is positively correlated with Aurora-A in colorectal cancer. Taken together, our data indicate hnRNP Q1 is a novel trans-acting factor that binds to Aurora-A mRNA 5’-UTRs and regulates its translation, which increases cell proliferation and contributes to tumorigenesis in colorectal cancer.
Citation Format: Liang-Yi Hung. HnRNP Q1 translationally increases the expression of Aurora-A and promotes tumorigenesis 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 4477. doi:10.1158/1538-7445.AM2017-4477
Abstract 4479: Cancer cell ribogenesis: MYC and the integrity of the RNA polymerase I-rRNA machinery
Authors: Rossetti Stefano , Wierzbicki Andrzej J. , Sacchi Nicoletta 
Published: July 2017

Abstract
Upregulation of RNA Polymerase (Pol I)-mediated transcription of ribosomal RNA (rRNA) and increased ribogenesis, which are necessary to sustain the increased metabolic demand of highly proliferating cancer cells, are hallmarks of cancer. Increased rRNA transcription can be due deregulation of tumor suppressors and oncogenes that affect Pol I activity. Overexpression of the MYC oncogene, a potent Pol I activators, is particularly frequent in cancer. In addition, based on our analysis of the Cancer Genome Atlas (TCGA), amplification/upregulation of genes encoding for basal components of the Pol I transcriptional machinery is also frequent in cancers of various histotype (Rossetti et al., Cell Cycle, 2016). By using breast and ovarian epithelial cells, we mechanistically found that: 1) ectopic expression of either MYC or RRN3 (TIF-IA), a key Pol I basal component, by increasing rRNA synthesis, is sufficient to induce in vitro transformation phenotypes and to promote cell proliferation; 2) there is a causal link between MYC overexpression and RRN3 upregulation; 3) MYC- or RRN3-induced rRNA upregulation sensitizes cells to the anti-proliferative action of drugs inhibiting rRNA transcription. Our findings provide a rationale for using drugs targeting rRNA transcription to curb proliferation of cancers cells due to rRNA upregulation by MYC.
Funding for this study was provided by an RPCI-UPCI Ovarian Cancer Spore DRP award (NS), the NCI R01 CA127614 grant (NS), the Terri Brodeur Breast Cancer Foundation (SR), the Susan Komen Foundation (SR), and the NCI P30 CA016056 institutional grant.
Citation Format: Stefano Rossetti, Andrzej J. Wierzbicki, Nicoletta Sacchi. Cancer cell ribogenesis: MYC and the integrity of the RNA polymerase I-rRNA machinery [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 4479. doi:10.1158/1538-7445.AM2017-4479