bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4962: ERG expression levels in prostate tumors reflect functional status of the androgen receptor as a consequence of fusion of ERG with AR regulated gene promoters
Authors: Mohamed Ahmed A. , Dobi Albert , Sun Chen , Shaheduzzaman Syed , Tan Shyh-Han , Petrovics Gyorgy , Hu Ying , Chen Yongmei , Furusato Bungo , Sesterhenn Isabell , Sreenath Taduru , McLeod David G. , Srivastava Shiv 
Published: February 2011

Abstract
Background: Androgen dependent overexpression of the TMPRSS2:ERG fusion is the most prevalent chromosomal rearrangement in prostate cancer. During our recent evaluations of the ERG downstream transcriptional targets, we identified 15-Hydroxyprostaglandin Dehydrogenase gene (HPGD) in response to ERG knock-down. HPGD is an enzyme that catalyzes the oxidation of prostaglandins and lipoxins by converting them into inactive keto-metabolites, and physiologically antagonizes COX-2, a prostaglandin-synthesizing enzyme. HPGD also behaves as a tumor suppressor in many cancers as overexpression of HPGD resulted in marked inhibition of cell growth. The objective of this study was to evaluate potential connection between ERG overexpression and prostaglandin signaling.
Experimental procedures: Small interference RNA (siRNA) oligo duplex was used to knock-down endogenous ERG and HPGD expressions. Western blot assay and Immunofluorescence was used to detect protein expressions. QT-PCR (normalized to GAPDH) was used for transcriptome analysis. GeneChip, Chromatin immunoprecipitation assays and cell proliferation assay were utilized for functional analysis.
Results: ERG knock-down in VCaP prostate tumor cells results in overexpression of HPGD, down regulation of the prostaglandin E2 receptor 4 (EP4), and inhibition of prostaglandin E2 induced Urokinase Plasminogen Activator (uPA) expression and cell growth. Comparison of HPGD between TMPRSS2:ERG positive and negative prostate tumors revealed a trend towards decreased HPGD expression in fusion positive tumors.
Conclusions: Taken together, these data suggest that ERG over-expression in CaP cells may positively influence prostaglandin mediated signaling. Funding sources: NIH Grants RO1 DK065977
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4962.
Abstract 4964: Transcriptional repression of MYCN is mediated by TAp63 in human neuroblastomas
Authors: Suenaga Yusuke , Kaneko Yoshiki , Yamamoto Mami , Matsumoto Daisuke , Ichikawa Tomoe , Moritan Toshiyuki , Kamijo Takehiko , Nakamura Yohko , Ohira Miki , Ozaki Toshinori , Nakagawara Akira 
Published: February 2011

Abstract
p53 is one of the major tumor suppressors and promotes apoptotic cell death by transcriptional activation of pro-apoptotic target genes. In malignant human tumors, however, its tumor suppressive activity is frequently inactivated by somatic mutation and/or chromosomal deletion. To enhance the efficacy of chemotherapeutic agents in p53-deficient tumors, it is necessary to elucidate the p53-independent mechanisms of apoptotic cell death.
Recently, we have shown that TATA-binding protein-like protein (TLP) transactivates one of p53 family members, TAp63, and induces apoptosis in a p53-independent manner. In response to DNA damage by etoposide, TLP is induced to translocate from cytoplasm to nucleus and enhance promoter activity of TAp63 through direct recruitment onto the promoter. TAp63 stimulated by TLP promotes apoptotic cell death in Hep3B cells null for the p53 alleles. The expression levels of TLP mRNA in human primary non-small lung cancers is low compared with corresponding normal tissues and the downregulation is significantly correlated with low levels of TAp63 and poor outcome of patients’ survival. These results suggest the potential for TLP-TAp63 pro-apoptotic pathway as a therapeutic target for malignant lung cancers.
In this study, we analyzed expression of p53 family genes in 106 primary neuroblastomas using quantitative real time RT-PCR, and found that the levels of only TAp63 expression was significantly high in favorable neuroblastomas as compared with unfavorable tumors (p=0.00696) and that its expression was inversely correlated with MYCN expression (p=0.0350). MYCN oncogene is frequently amplified and overexpressed in unfavorable neuroblastoma, and in vitro studies have demonstrated that downregulation of MYCN is the critical steps for neuronal cell death induced by retinoic acids (RA) regardless of p53 status in tumors. However, the precise molecular mechanisms of the down-regulation of MYCN by RA have not been elusive. Intriguingly, TLP and TAp63 are induced in response to RA treatment and TAp63 directly represses MYCN transcription. In addition, RA treatment also inhibits positive auto-regulation of MYCN, leading to further down-regulation of MYCN mRNA levels.
Collectively, our results suggest that TAp63 is highly expressed in favorable neuroblastomas and contributes to repression of MYCN by RA treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4964.
Abstract 4976: Crif1, a new negative regulator of Nrf2
Authors: Bae Insoo , Kang Hyo Jin , Kim Hee Jeong , Hong Yong Bin , Chang Young Soo 
Published: February 2011

Abstract
Abstract
Free radicals generated by oxidative stress cause damage that can contribute to numerous chronic diseases. Mammalian cells respond to this damage by increased transcription of cytoprotective phase II genes, which are regulated by Nrf2. Previously, it has been shown that Nrf2 protein levels increase after oxidative stress because its negative regulator, Keap1, loses its ability to bind Nrf2 and cause its proteasomal-mediated degradation during oxidative stress. Here, we show that Crif1 is also able to negatively regulate Nrf2 protein stability. However, and in contrast to Keap1, which regulates Nrf2 stability only under normal reducing conditions, Crif1 regulates Nrf2 stability, accumulation and target gene expression under both reducing and oxidative stress conditions. Thus, Crif1-Nrf2 interactions and their consequences are redox-independent. In addition, Crif1, but not Keap1 (which only interacts with N-terminal region of Nrf2), physically interacts with both N- and C-terminal regions of Nrf2 and promote Nrf2 ubiquitination and proteasomal-mediated degradation. Finally, Crif1 can modulate cells’ sensitivity to oxidative stress-induced cytotoxicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4976.
Abstract 4980: Myocardin functions as an effective inducer of growth arrest and differentiation in human leiomyosarcoma cells
Authors: Kimura Yasunori , Morita Tsuyoshi , Hayashi Ken'ichiro , Miki Tsuneharu , Sobue Kenji 
Published: February 2011

Abstract
Myocardin is an important transcriptional regulator in smooth and cardiac muscle development. We noticed that the expression of myocardin was markedly downregulated in human uterine leiomyosarcoma cells. Restoration of myocardin expression induced the re-expression of smooth muscle marker proteins and the formation of well-developed actin fibers. A concomitant increase in the expression of a CDK inhibitor, p21, led to a significant slowing of cell proliferation, via p21's inhibition of the G1/S transition. A p21 promoter-reporter assay showed that myocardin markedly increased p21's promoter activity. Furthermore, a serum response factor (SRF)-binding cis-element CArG-box in the p21 promoter region was required for this myocardin effect. Chromatin immunoprecipitation and DNA-protein binding assays showed that myocardin indirectly bound to the CArG-box in the p21 promoter through an interaction with SRF. Furthermore, immunohistochemistry revealed that the levels of myocardin and p21 were both lower in leiomyosarcoma samples than in normal smooth muscle tissue. Taken together, our results indicate that the downregulation of myocardin expression facilitates cell-cycle progression via the reduction of p21 expression in human leimyosarcomas, and suggest that myocardin could be a useful therapeutic target for this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4980.
Abstract 4994: Association of protein inhibitor of activated STAT protein 4 with the development of pancreatic ductal adenocarcinoma identified by chromosomal analysis from single nucleotide polymorphism arrays
Authors: Chien Wenwen , Kawamata Norihiko , Okemoto Kazu , Ogawa Seishi , Koeffler H. Phillip 
Published: February 2011

Abstract
The purpose of this study is to identify novel genomic alterations in pancreatic ductal adenocarcinoma (PDAC) by single nucleotide polymorphism arrays (SNP-chip). Genomic DNA from 12 tissues and 15 cell lines of PDAC was examined using 250K SNP-chip. Regions with gains and losses of DNA copy number and loss of heterozygosity (LOH) were identified. Additional 10 normal and 6 tumor samples were used in quantitative real-time PCR to validate a subset of genes in the region with copy number alterations. Our results were compared with previously reported data. Frequent gains of chromosomes: 1q, 2, 3q, 5, 7, 8q, 11, 12p, 14, 17q and 20q (&gt;50% of cases) and losses of 8p, 9p and 18q (&gt;33% of cases) were detected. LOH regions were identified in chromosome arms: 6p, 6q, 8p, 9p, 9q, 13q, 17p, 18q, 19p, 19q and 21q (&gt;25% of cases). On 19p LOH region, a common deletion occurred at 19p13 which included the gene known as protein inhibitor of activated STAT protein 4 (PIAS4). The deletion of the gene and expression levels of PIAS4 were correlated in the PDAC samples. The effects of exogenous over-expression of PIAS4 and short hairpin RNA (shRNA)-mediated knockdown of endogenous PIAS4 on cell proliferation and apoptosis were examined, as well as identification of cell signaling pathway linking PIAS4 and pancreatic tumorigenesis. Over-expression of PIAS4 decreased pancreatic cancer cell growth as well as decreased expression of genes involved in cell proliferation such as Bcl-2, Bcl-xL, cyclin D1 and XIAP. Activated PIAS4 decreased glycogen synthase kinase 3beta (GSK3beta) activity and inhibited transcriptional activity of nuclear factor kappa B (NFkB). Our data indicated that deletion of PIAS4 is associated with development of PDAC. Mechanistic studies showed that PIAS4 acted as a tumor suppressor gene and was a novel modulator of GSK3beta signaling in pancreatic tumorigenesis.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4994.
Abstract 5008: Loss of DEC1 (Deleted in esophageal cancer 1) during esophageal cancer progression and functional characterization of its downstream target
Authors: Wong Victor CL , Qi Robert Z. , Chan Kwok Wah , Li Ping Jun , Wang Li Dong , Li Ji Lin , Law Simon , Tsao Sai Wah , Lung Maria Li 
Published: February 2011

Abstract
Background and aims: Deleted in esophageal cancer1 (DEC1) is a frequently down-regulated candidate tumor suppressor gene in esophageal cancer (EC). We previously showed that this gene can suppress tumor growth and up-regulate Dual specificity phosphatase 6 (DUSP6), as a downstream target of DEC1, in esophageal squamous cell carcinoma (ESCC). In this study, we attempt to detect the expression of DEC1 during cancer progression and to identify subcellular localization of DEC1. We also evaluated the tumor suppressive role of DUSP6 in tumor development. Methods: As yet, there are no other published studies of DEC1 protein. Thus, DEC1-specific polyclonal antibody was generated and utilized for Western blotting, tissue microarray study, and immunostaining. We utilized cell functional assays such as colony formation, cell proliferation, and wound healing assays, as tools to evaluate tumor suppressive role of DUSP6. Results: Loss of DEC1 expression is observed in ESCC tumors, as compared to their matched normal counterparts in Western blot analysis. Significant loss of DEC1 during cancer progression was found. The expression of DEC1 is significantly related to cancer family history and age of patients. By immunostaining, DEC1 was localized to the cytoplasm, nucleus, and perinuclear region. In addition, we observed an important role of DUSP6 in suppressing cell growth and migration. Conclusions: We further validated the crucial role of DEC1 expression in EC tumorigenesis by use of tissue microarray. We identified subcellular localization of DEC1, providing a basis for further study of the tumor suppressive mechanism of DEC1. In addition, a tumor suppressive role of DUSP6 was confirmed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5008.
Abstract 5012: REST is lost in aggressive breast cancer through an aberrant splicing loop
Authors: Wagoner Matthew P. , Gunsalus Kearney TW , Schoenike Barry , Dang Christina , Alexander Caroline M. , Richardson Andrea L. , Friedl Andreas , Roopra Avtar 
Published: February 2011

Abstract
Transcriptional profiling of breast tumors has lead to new diagnostic tools allowing better prediction of disease recurrence and response to treatment, but does little to elucidate mechanisms responsible for the differential disease course. Using transcriptional profiling we show for the first time that a subset of breast tumors lack the tumor suppressor RE1 silencing transcription factor (REST), a master repressor of neuronal genes. Loss of REST is sufficient to induce anchorage independent cell growth in human mammary epithelial cells, and we find that these REST-less tumors show a highly aggressive disease course independent of tumors grade, size or subtype. Importantly, these aggressive tumors overexpress the tumor promoter and REST target gene Lin28, which may be responsible for the aggressive phenotype of these tumors (Gunsalus et al. poster, AACR 2010 CB4). We find that loss of REST function occurs in breast cancer via alternative splicing of the tumor suppressor to a truncated form normally observed in the brain following seizures. Here, we show that REST regulates its own aberrant splicing in an intriguing positive-feedback loop that results in a loss of REST function. These results identify a previously unknown subset of aggressive cancers, the transcription factor responsible for unique molecular profile, and the novel positive feedback pathway responsible for the aberrant splicing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5012.
Abstract 5022: Roles of endoplasmic reticulum factor ERLIN2 in malignancy maintenance and therapy resistance in breast cancer
Authors: Wang Guohui , Liu Gang , Ethier Stephen P. , Zhang Kezhong , Yang Zeng-Quan 
Published: February 2011

Abstract
Endoplasmic reticulum (ER)-associated degradation (ERAD) components are highly induced in various tumors and are associated with cancer cell survival and resistance to anti-cancer treatments. The ERAD pathway is crucial for the cell to adapt to ER stress by degrading misfolded, unassembled and even some normal proteins in the ER lumen. Recent work in our group has led us to identify the ER lipid raft-associated 2 (ERLIN2, also known as SPFH2, C8ORF2) gene as one of the candidate oncogenes within the 8p11-12 amplicon in breast cancer based on statistical analysis of copy number increase and over expression. ERLIN2 protein, which localized specifically to the ER, is the key component of ERAD pathway. To elucidate the oncogenic properties of the ERAD factor ERLIN2 in human breast cancer, we established the MCF10A-ERLIN2 cell line, which stably over expresses ERLIN2 in human nontransformed mammary epithelial cells (MCF10A) using the pLenti6/V5-ERLIN2 construct. ERLIN2 over expressing cells and their respective parental cell lines were assayed for alterations in growth rates, growth factor-independent proliferation and other phenotypes expressed by cancer cells. From these experiments, we found that over expression of ERLIN2 in MCF10A cells results in growth factor-independent proliferation in insulin-like growth factor deficient media and formed large, highly-proliferative, and abnormally-structured colonies in three-dimensional morphogenesis assays. However, over expression of ERLIN2 in MCF10A cells did not result in cells with anchorage independent growth potential. To further elucidate the molecular basis that ERLIN2 is linked to the ER-stress response pathways in breast cancer cells, we knocked down the ER stress sensor IRE1α activity in the breast cancer cell lines in which ERLIN2 is amplified and over expressed. The knockdown of the IRE1α RNase activity, but not the kinase activity, significantly reduced protein levels of ERLIN2 in ERLIN2 amplified breast cancer cells. In addition, forced expression of wild-type IRE1α or spliced XBP1, the IRE1α target, led to increased expression of ERLIN2 in MCF10A cells. We also found that ERLIN2 protein was induced in response to the ER stress-inducing reagents Tunicamycin, Thapsigargin or growth factor depletion. Together, our findings indicate that ERLIN2 plays an unconventional oncogenic role through modulating ER stress response and ERAD pathways in a subset of breast cancer. Targeted inhibition of ERAD factor ERLIN2 in cancer could provide potential new avenues for therapeutic development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5022.
Abstract 5029: RasGRP3- a new therapeutic target in human melanoma
Authors: Yang Dazhi , Juan Tao , Kedei Noemi , Li Luowei , Yuspa Stuart , Blumberg Peter 
Published: February 2011

Abstract
RasGRP3, a RasGEF (Ras guanine nucleotide exchange factor), is an activator of H-Ras, R-ras and Rap1, Here, we report that its expression level was increased in multiple human melanoma cell lines, reaching a level of protein expression approaching that of Ramos cells in the case of the SK-MEL-5 melanoma line. Likewise, RasGRP3 expression was variably elevated in human melanoma tissue samples. The importance of RasGRP3 expression for the melanoma cell lines was demonstrated by down regulating its expression, which inhibited cell proliferation and blocked both colony formation in soft agar and xenograft tumor formation in immunodeficient mice in the case of both the M14 and SK-Mel-5 cell lines. Finally, RasGRP3 was involved in downstream signaling in these cells. Suppression of RasGRP3 expression reduced both basal and HGF induced AKT phosphorylation in the M14 and SK-Mel-5 cells. Consistent with these results, we found that overexpression of RasGRP3 in human primary melanocytes changed their morphology, enhanced cell proliferation, and caused xenograft tumor formation. Suppression of the RasGRP3 overexpression in these cells inhibited downstream RasGRP3 responses and suppressed cell growth, confirming the functional role of RasGRP3 in the altered behavior of these cells. We conclude that RasGRP3 represents a potential therapeutic target in melanoma. Even more generally, the high level of expression and functional role of RasGRP3 in melanoma emphasizes that this RasGEF may play a more general role in regulation of Ras family members than had been initially appreciated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5029.
Abstract 5032: MK8745, an Aurora A kinase-specific inhibitor induces apoptosis in a p53-dependent manner
Authors: Nair Jayasree S. , Schwartz Gary K. 
Published: February 2011

Abstract
Aurora kinases are mitotic serine/threonine protein kinases and are attractive novel targets for anticancer therapy. Many small molecule inhibitors are being developed and few are currently undergoing clinical trials. Aurora A kinase is essential for the successful mitotic transition. MK8745 is a novel and selective small molecule inhibitor of Aurora A kinase. Treatment of tumor cells with MK8745 (1 to 5 µM) resulted in accumulation of cells in mitosis with an increase in Aurora A expression. Despite this increase in Aurora A in the cells, dose dependent inhibition of Aurora A kinase activity was confirmed by an in vitro kinase assay using a PLK1, a specific substrate of Aurora A kinase. Also, treatment of HCT116 (p53−/−) cells ectopically overexpressing wild type p53 with MK8745 showed a decrease in phospho p53 (ser315), another known substrate of Aurora A. We then explored the mechanism by which MK8745 induces proliferation inhibition in cell lines of multiple lineages such as colon, melanoma, sarcoma and pancreatic according to p53 status. In general, the cell lines expressing wild type p53 showed a short delay in mitosis followed by cytokinesis with significant apoptosis (15%) upon exposure to MK8745. However, cell lines with null or mutant p53 underwent endoreduplication resulting in 60% polyploidy after a prolonged delay in mitosis with no apoptosis. This was further confirmed in the isogenic HCT-116 cell lines such that HCT p53−/− cells underwent polyploidy, whereas HCT p53 +/+ and the HCT p21 −/− cells underwent apoptosis. Under all of these conditions phospho histone H3 (Ser10) was not inhibited, indicating these phenotypic effects are a result of Aurora A inhibition and not Aurora B. P53 dependence for apoptosis was also confirmed in p53 null cells overexpressing wild type p53. Transient knock down of Aurora A kinase by specific SiRNA resulted in high levels of apoptosis and again showed p53 dependence. These results suggest that determining the p53 status may be important when using Aurora A kinase targeted therapies in the clinic. Further studies are underway to determine the role of p53 in the induction of apoptosis that results from inhibition of Aurora A kinase.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5032.