bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1325: Profilin-1 overexpression downregulates phosphorylation of p27kip1 leading to its nuclear accumulation in breast cancer cells
Authors: Jiang Chang , Veon William , Roy Partha 
Published: May 2015

Abstract
Profilin-1 is a ubiquitously expressed actin-binding protein that is downregulated in human breast cancer. Overexpression of profilin-1 in human breast cancer cells suppresses their tumorigenic potential. We had previously shown that profilin-1 overexpression elevates the expression level of p27kip1 leading to cell-cycle arrest in G1 phase. In the present work, we explore the underlying mechanism. Our studies showed that profilin-1-induced accumulation of p27kip1 in breast cancer cells occurs most dramatically in the nuclear compartment and this is due to impaired protein degradation. Consistent with these observations, we found that phosphorylation of p27kip1 at T187 (a prerequisite for p27kip1 degradation by SCF-Skp2 complex in the nucleus) and S10 (a post-translational event that promotes nuclear export of p27kip1) residues are both significantly inhibited by profilin-1 overexpression. Elevating profilin-1 level suppresses AKT activation, and hyper-activating AKT through overexpression of a constitutively active mutant relieves profilin-1-induced inhibition of T187 phosphorylation and elevation of p27kip1. These data demonstrate that profilin-1 can control the cellular level of p27kip1 in breast cancer cells through affecting its post-translational modification in an AKT-dependent pathway. These findings may provide mechanistic insights underlying the tumor-suppressive action of profilin-1.
Citation Format: Chang Jiang, William Veon, Partha Roy. Profilin-1 overexpression downregulates phosphorylation of p27kip1 leading to its nuclear accumulation in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1325. doi:10.1158/1538-7445.AM2014-1325
Abstract 1349: Chemosensitization of breast cancer cell lines by Ell3
Authors: Ahn Hee-Jin , Heo Sun-Hee , Kim Gwangil , Park Kyung-Soon 
Published: May 2015

Abstract
Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven-nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis by the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. Contrary to our expectation, ectopic expression of Ell3 in MCF7 induces CDDP (cisplatin) susceptibility by enhancing p53 dependent apoptosis. CDDP treatments leads to the accumulation of p53 protein in the Ell3 overexpressing MCF7. We confirmed that Ell3 inhibits proteosomal degradation of p53 upon cisplatin treatment in MCF7. Ell3 also confer chemosensitivity to MCF7 to DNA damaging agent, camptothecin. The treatment of camptothecin to Ell3 overexpressing MCF7 results in the accumulation of cells at G2/M phase of cell cycle by the increases of p53 protein. Consistent with these results, Ell3 downregulates the expression of MDM2, which binds p53 and marks it for degradation using the proteasome. The underlying mechanism of Ell3 to regulate MDM2 expression is under investigation.
Citation Format: Hee-Jin Ahn, Sun-Hee Heo, Gwangil Kim, Kyung-Soon Park. Chemosensitization of breast cancer cell lines by Ell3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1349. doi:10.1158/1538-7445.AM2014-1349
Abstract 1373: Comprehensive analysis of HBV DNA methylation in liver tissues of hepatitis B, cirrhosis and hepatocellular carcinoma patients
Authors: Jain Surbhi , Chen Sitong , Boldbaatar Batbold , Lin Selena Y. , Yan Ran , Hu Chi-Tan , Guo Haitao , Block Timothy M. , song Wei , Su Ying-Hsiu 
Published: May 2015

Abstract
Hepatitis B virus (HBV) is a hepatotropic virus causing hepatitis, cirrhosis and hepatocellular carcinoma. In patients, HBV DNA circulates in blood as virion DNA and exists in hepatocytes both as nuclear form (episomal cccDNA and integrated DNA) and as cytoplasmic core DNA form. It has been reported that HBV infection up-regulates DNMTs and thus induces epigenetic changes in the host cells. Understanding the methylation status of the HBV DNA in its different forms can potentially provide insight into the pathogenesis of HBV-related liver diseases including hepatocarcinogenesis. Previous studies conducted in patient serum and in cell cultures have demonstrated that the CpG islands of HBV virion DNA are in the unmethylated state, and cccDNA methylation has been extensively studied for its role in the regulation of transcription, but very few studies have investigated the methylation status of integrated HBV DNA in human liver tissues. To better understand the methylation status of HBV DNA in hepatitis B, cirrhosis and HCC, a comprehensive methylation profile of three CpG islands in the HBV genome was assessed by BS-sequencing, and methylation of each of the 3 CpG islands was compared by using bisulfite specific PCR and methylation specific PCR assays in a larger sample size. We observed that the methylation of CpG island 1 and 3 of HBV DNA from liver tissues was significantly higher in HCC as compared to hepatitis and cirrhosis. We also obtained, for the first time, the evidence of rare non-CpG methylation in the CpG island 1 and 2 of HBV genome in liver tissues. The overall co-relation of HBV genome methylation and disease progression was also investigated. In addition, no co-relation between the methylation levels of the HBV genome and host genome was found, suggesting independent mechanisms regulate the methylation of host and viral genomes. The mechanisms of HBV genome methylation in liver disease and its regulation are discussed.
Citation Format: Surbhi Jain, Sitong Chen, Batbold Boldbaatar, Selena Y. Lin, Ran Yan, Chi-Tan Hu, Haitao Guo, Timothy M. Block, Wei song, Ying-Hsiu Su. Comprehensive analysis of HBV DNA methylation in liver tissues of hepatitis B, cirrhosis and hepatocellular carcinoma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1373. doi:10.1158/1538-7445.AM2014-1373
Abstract 1388: Biological role of novel NQO2 inhibitors in cancer therapeutics
Authors: Santina Elham , Chadwick Amy , Nabulsi Soraya A. , Freeman Sally , Demonacos Constantinos , Stratford Ian 
Published: May 2015

Abstract
Background: NRH: quinone oxidoreductase 2 (NQO2), is a cytosolic flavoprotein that catalyses the two-electron reduction of quinones into hydroquinones. The physiological role of NQO2 in cancer biology is still not well understood. Some studies have suggested that inhibiting NQO2 could have a great potential in chemoprevention. This is based on the observation that NQO2 gene knockdown promotes protection against the toxicity of quinones such as menadione.
Aim: To evaluate the biological role of novel NQO2 inhibitors in cancer therapeutics. Novel inhibitors will be used as pharmacological tools to study the physiological role of NQO2 in cancer cells, and to identify the consequences of inhibiting NQO2 on the tumor microenvironment.
Methods: Novel compounds with diverse structures have been tested for their inhibition of NQO2 enzymatic activity in a cell-free system using a pure enzyme assay. The functional activity of these compounds as NQO2 inhibitors in the MDA-MB 231 breast cancer cells was also assessed. The effect of these inhibitors on the cellular proliferation of MDA-MB 231 breast cancer cells was tested using an MTT assay. Off-target (DNA binding) effects were analyzed by measuring the DNA thermal temperature. Moreover, the effect of these inhibitors on modulating TNFα-mediated NF-kB transcriptional activity was tested and the mechanism behind this modulation was also examined.
Results: The novel inhibitors tested resulted in the inhibition of NQO2 activity in the cell free and the cellular system at nano-molar concentrations .Inhibition of MDA-MB 231 cell proliferation was also witnessed at low micro-molar concentrations. The inhibitors also displayed no DNA binding ability. In addition, the inhibitors were able to attenuate TNFα-mediated NF-kB transcriptional activity by blocking the phosphorylation of IkBα. This has resulted in the suppression of cell growth and promotion of cell apoptosis.
Conclusions: This study has demonstrated novel potent inhibitors of NQO2 that are functionally active in the cells at nano-molar concentrations. The effect of the inhibitors on TNFα-mediated NF-kB transcriptional activity raises the possibility that inhibiting NQO2 could modulate the tumor micro-environmental factors, such as metastasis and angiogenesis.
Citation Format: Elham Santina, Amy Chadwick, Soraya Al Nabulsi, Sally Freeman, Constantinos Demonacos, Ian Stratford. Biological role of novel NQO2 inhibitors in cancer therapeutics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1388. doi:10.1158/1538-7445.AM2014-1388
Abstract 1389: Insights into the invasiveness of triple-negative breast cancer from genome-wide profiling of AP-1
Authors: Zhao Chunyan , Qiao Yichun , Dahlman-Wright Karin 
Published: May 2015

Abstract
Triple-negative breast cancer (TNBC) is an aggressive clinical phenotype, and accounts for 15% to 20% of all breast cancers. The molecular determinants of malignant cell behaviors in TNBC remain largely unknown. We show that the AP-1 transcription factor component Fra-1 is overexpressed in basal-like breast tumors, often referred to as TNBCs, and that its expression level has high prognostic significance. Depletion of Fra-1 or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Furthermore, knockdown of Fra-1 or c-Jun also reduces cellular invasion in vivo in a zebrafish xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we provide insights into the transcriptional regulatory networks of AP-1 in TNBC cells. We identify direct targets of the Fra-1/c-Jun heterodimer involved in cell proliferation, cell adhesion, and cell-cell contact. Importantly, we show that AP-1 represses E-cadherin expression by transcriptional upregulation of ZEB2, thereby stimulating cell invasion. This work sheds light on mechanisms and pathways by which TNBCs acquire invasiveness and proliferative propensity.
Note: This abstract was not presented at the meeting.
Citation Format: Chunyan Zhao, Yichun Qiao, Karin Dahlman-Wright. Insights into the invasiveness of triple-negative breast cancer from genome-wide profiling of AP-1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1389. doi:10.1158/1538-7445.AM2014-1389
Abstract 1391: SOX2-p63 interaction and genomic co-localization in squamous cell carcinomas
Authors: Watanabe Hideo , Ma Qiuping , Peng Shouyong , Adelmant Guillaume , Swain Danielle , Song Wenyu , Fox Cameron , Francis Joshua M. , Pedamallu Chandra Sekhar , Deluca David S. , Brooks Angela N. , Que Jianwen , Rustgi Anil K. , Wong Kwok-kin , Ligon Keith L. , Liu X. Shirley , Marto Jarrod A. , Meyerson Matthew , Bass Adam J. 
Published: May 2015

Abstract
SOX2 is a transcription factor essential for pluripotent stem cells and the development and maintenance of squamous epithelium. We previously reported SOX2 to be an oncogene subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we aim to further characterize SOX2's function in SCC. We demonstrate that SOX2 binds to distinct genomic loci in SCCs than in embryonic stem (ES) cells through comparative ChIP-seq analysis. Through mass-spectrometric analysis following tandem-affinity immunopurification in SCCs we identify SOX2 interacts with another master squamous transcription factor, p63, instead of its partner in ES cells, OCT4. We find that genomic occupancy of SOX2 in SCC overlaps with that of p63 at a large number of loci and this SOX2-p63 coordinate binding is absent in ES cells. We further demonstrate that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which we find essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that SOX2's actions in SCC differ substantially from its role in pluripotency. The identification of novel SOX2-p63 interaction enables deeper characterization of SOX2's function in SCC and normal squamous epithelial physiology.
Citation Format: Hideo Watanabe, Qiuping Ma, Shouyong Peng, Guillaume Adelmant, Danielle Swain, Wenyu Song, Cameron Fox, Joshua M. Francis, Chandra Sekhar Pedamallu, David S. Deluca, Angela N. Brooks, Jianwen Que, Anil K. Rustgi, Kwok-kin Wong, Keith L. Ligon, X. Shirley Liu, Jarrod A. Marto, Matthew Meyerson, Adam J. Bass. SOX2-p63 interaction and genomic co-localization in squamous cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1391. doi:10.1158/1538-7445.AM2014-1391
Abstract 1393: Correlating the expression of protein kinase C isozymes with the transformed phenotype in colorectal cancer
Authors: Dowling Catríona M. , Hanly Jennifer , Dalton Tara , Kiely Patrick A. 
Published: May 2015

Abstract
Protein Kinase C (PKC) is a family of serine/threonine kinases that are involved in almost every signal transduction pathway. Their regulation is mediated by several factors and by binding to a group of scaffolding proteins called RACKs (Adams et al. 2011). The development of PKC modulators with anti-cancer therapeutic value is a major target in cancer. However, this task is made difficult because PKC has an important role to play in normal processes and the PKC family consists of at least 12 different isozymes. In colon cancer, there is differential expression of the PKC isozymes, giving the cancer cells a migratory advantage and thus promote cancer progression. Our hypothesis is that PKC expression, activity and localisation are altered as colon epithelial cells switch from normal to the transformed state. We are confident that being able to recognise these changes has the potential to be used as a biomarker and prognostic marker in the early detection of colon cancer. Using novel 3D culture techniques, we examined the gene expression pattern of the 12 different PKC isozymes. We found that the isozymes were differentially expressed and that their expression pattern changed depending on whether the cells were grown under 2-dimensional or 3-dimensional culture systems. Using patient samples, we also document differential expression of several isozymes when compared to matched normal tissue. Using a series of PKC activators, together with a series of synergistic cellular and molecular approaches, we follow the migration of specific PKC isoforms to the membrane fraction in cells. This migration is dependent on the expression of RACK1 as when we use siRNA against RACK1, we disrupt PKC translocation in colon cancer cells. Taken together, our findings confirm that there is differential expression of PKC isozymes in cancer cells. We also confirm that specific PKC isozymes colocalise with RACK1 at the membrane supporting our hypothesis that RACK1 plays a central role in translocating PKC in the colon epithelium. Differential PKC expression and PKC translocation may be an important mechanism regulating the transformed phenotype of colon cancer cells.
Citation Format: Catríona M. Dowling, Jennifer Hanly, Tara Dalton, Patrick A. Kiely. Correlating the expression of protein kinase C isozymes with the transformed phenotype in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1393. doi:10.1158/1538-7445.AM2014-1393
Abstract 1394: Role of non-coding RNA in regulation of stemness and differentiation via notch signaling pathway in glioblastoma
Authors: Katsushima Keisuke , Shinjo Keiko , Ohka Fumiharu , Natsume Atsushi , Shibata Tatsuhiro , Kondo Yutaka 
Published: May 2015

Abstract
Multiple distinct subpopulations of cancer cells within tumors may derive from a limited source of cancer cells, called cancer stem cells (CSCs), which may have plasticity and respond to signals from their microenvironment. Recent studies demonstrated the fundamental roles of long non-coding RNA (lncRNA) in various biological processes. Here, we investigated the roles of lncRNA in glioma stem cells (GSCs) differentiation. Whole-genome RNA sequencing revealed that 180 and 171 lncRNAs were commonly upregulated and downregulated with a greater than 2-fold difference in GSC differentiation, respectively. Among those, linc-A was consistently downregulated during GSC differentiation. Linc-A, of which expression is regulated by the Notch signaling pathway, physically interacted with polycomb repressive complex 2 (PRC2) and conferred a recruitment of PRC2 and histone H3 lysine 27 trimethylation (H3K27me3) in its target loci. An RNA pull-down assay revealed that linc-A specifically bound to a number of neuronal differentiation-associated genes in GSC. These target genes were consistently silenced in GSCs. Inhibition of linc-A using antisense oligonucleotide reduced the H3K27me3 level and increased expression of its target genes, resulted in loss of stemness and induction of GSC differentiation into neuronal lineage. Intriguingly, in silico analysis revealed that linc-A shared a sequence of microRNA-response element (MRE) with mRNAs of stemness markers, such as MYC, SOX2, and NANOG. Indeed, downregulation of linc-A increased the miR-X expression together with repression of its target genes, MYC, SOX2, and NANOG, being consistent with an RNA sponge mechanism, in which lncRNAs contain complementary binding sites (MRE) to a miRNA of interest and prevent these mRNAs from degradation. Our data indicated that linc-A plays consistent roles in modulation of stemness properties in GSC in response to Notch-epigenetic regulatory pathway.
Citation Format: Keisuke Katsushima, Keiko Shinjo, Fumiharu Ohka, Atsushi Natsume, Tatsuhiro Shibata, Yutaka Kondo. Role of non-coding RNA in regulation of stemness and differentiation via notch signaling pathway in glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1394. doi:10.1158/1538-7445.AM2014-1394
Abstract 1424: Enhanced pyruvate carboxylation is crucial to non-small cell lung cancer proliferation and anabolism
Authors: Sellers Katherine E. , Fox Matthew P. , Bousamra Michael , Yan Jun , Yuneva Mariia , Higashi Richard M. , Lane Andrew N. , Fan Teresa W. 
Published: May 2015

Abstract
Proliferating cancer cells require an active Krebs cycle for generating anabolic precursors, in addition to energy production. Diversion of the Krebs cycle intermediates to meet anabolic demands cannot be sustained without anaplerosis. The two major anaplerotic pathways are the deamidation of glutamine to form glutamate catalyzed by glutaminase (GLS) or glutaminolysis, and the carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC).
We determined the expression of PC and GLS proteins in fresh tumor tissue and paired adjacent benign tissue from 86 human NSCLC patients. PC was elevated (median 8-10 fold) in 94% of the tumor tissues, whereas GLS expression did not differ significantly between tumor and paired non tumorous lung tissue. Using 13C6 glucose as tracer and stable isotope-resolved metabolomics (SIRM), we also observed elevated PC activity in vivo in human patients with early stage NSCLC. To examine the importance of PC in the growth and survival of NSCLC, 5 NSCLC cell lines were transduced with a lentiviral vector containing an shRNA against PC. PC knockdown slowed proliferation, induced multinucleation, and reduced colony formation in soft agar. To validate attenuated PC activity and to profile the metabolic effect of PC knockdown, A549 cells were grown in 13C6 glucose or 13C5 glutamine and the incorporation of 13C into various metabolic pathways was measured by NMR and MS by SIRM. We found reduced entry of both glucose and glutamine carbon into the Krebs cycle metabolites, fatty acyl chains of lipids, and nucleotides, suggesting that both energy production and anabolic pathways were hindered and blocking the PC pathway was not compensated by GLS activity. In addition, glutathione biosynthesis and homeostasis were perturbed by PC suppression, leading to compromised anti-oxidation capacity. We further found that PC knockdown in A549 cells reduced their growth rate in mouse xenografts, and recapitulate the metabolic perturbations seen both in cell culture and in human patients. Together, these results suggest that PC is indispensible for the growth and anabolism of NSCLC.
This work was funded by 5P20RR018733, 1R01CA118434-01A2, 1P01CA163223-01A1, 1R01ES022191-01, and 3R01CA118434-02S1; and the KLCRP, CTSPGP, and the KY Challenge for Excellence.
Citation Format: Katherine E. Sellers, Matthew P. Fox, Michael Bousamra, Jun Yan, Mariia Yuneva, Richard M. Higashi, Andrew N. Lane, Teresa WM Fan. Enhanced pyruvate carboxylation is crucial to non-small cell lung cancer proliferation and anabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1424. doi:10.1158/1538-7445.AM2014-1424