bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2169: The effect of WT1 on E-cadherin expression in prostate cancer cells
Authors: Brett Adina , Fraizer Gail , Eisermann Kurtis 
Published: June 2012

Abstract
Prostate carcinoma is the most common malignancy and second leading cause of death among American men. The molecular mechanisms that control the progression of this type of cancer are still poorly understood. One of the genes expressed in prostate cancer epithelium is the zinc finger transcription factor Wilms’ Tumor 1, WT1. Previous studies in our lab have shown WT1 protein in a majority of high grade prostate tumor sections with little or no WT1 staining in non-neoplastic or benign prostatic hyperplasia (BPH) tissues. However, a mechanistic role for WT1 in prostate cancer has not been established. Recently, WT1 has been associated with the regulation of cell adhesion molecules such as E-cadherin in NIH 3T3 cells and epicardial cells. Loss of E-cadherin expression is frequently associated with increased cellular motility and tumor invasion. Several regulatory mechanisms controlling E-cadherin gene expression have been proposed in breast cancer cells, however the mechanisms of regulation of E-cadherin gene expression in prostate cancer cells are not yet understood. The objective of this study was to determine whether WT1 might regulate E-cadherin expression and contribute to cancer progression in prostate cancer cells. First, potential WT1 binding sites were identified in the promoter of the E-cadherin gene using a bioinformatics approach. Chromatin Immunoprecipitation (ChIP) showed direct in vivo binding of WT1 to the E-cadherin promoter in the chromatin of LNCaP and PC3 cells. The effect of transfection of prostate cancer cells with a GFP/WT1 expression construct was then tested by quantitative real-time PCR (QRT-PCR). QRT-PCR results showed a decrease in E-cadherin transcripts in GFP/WT1 transfected prostate cancer cells. Conversely, knockdown of WT1 mRNA in siWT1 transfected LNCaP cells, showed increased levels of E-cadherin mRNA. Moreover, co-transfection of WT1 expression construct with an E-cadherin promoter reporter construct showed that WT1 decreased the activity of the proximal E-cadherin promoter in PC3 cells. Overall these results demonstrated that WT1 modulated E-cadherin expression in prostate cancer cells and suggests a novel mechanism whereby WT1 may increase migration by decreasing E-cadherin levels, a novel role for WT1 mediated prostate cancer progression.
This work was supported by NIHR15CA11360 and Ohio Board of Regents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2169. doi:10.1158/1538-7445.AM2011-2169
Abstract 217: Functional analysis of the protein citrullination through p53/PADI4 network in carcinogenesis
Authors: Tanikawa Chizu , Matsuda Koichi , Nakamura Yusuke 
Published: June 2012

Abstract
Upon a wide range of cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes related to apoptosis, cell cycle arrest, and DNA repair. However, its involvement in posttranslational modifications of proteins has not yet been well characterized. We recently reported the novel role of p53 in the regulation of protein citrullination through the transactivation of peptidylarginine deiminase type 4 (PADI4). The PADI4 gene encodes an enzyme catalyzing the citrullination of arginine residues in proteins, and ectopic expression of p53 or PADI4 induced protein citrullination. In addition, various proteins were citrullinated in response to DNA damage, but knockdown of PADI4 or p53 remarkably inhibited their citrullination. Here we generated the Padi4-deficient mice and examined the role of protein citrullination in vivo. When mice were exposed to X-ray (3 Gy), Padi4 expression was induced in thymus of irradiated wild type mice but not in p53-/- and Padi4-/- mice. Interestingly, TUNEL-positive cells in irradiated thymus were significantly decreased in Padi4-/- mice. Gene expression analysis using irradiated thymus tissues revealed several genes related to the immune response were regulated by Padi4. To further investigate the molecular mechanism whereby PADI4 regulates apoptotic pathway, we surveyed PADI4 substrates and found that various proteins such as core histones were citrullinated in response to DNA damage. These findings demonstrated the significance of PADI4-mediated protein citrullination in the p53 signaling pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 217. doi:10.1158/1538-7445.AM2011-217
Abstract 2178: Survivin appears to act as a transcription factor or co-factor to transcriptionally downregulate p21 gene expression via a p53 status-dependent manner
Authors: Tang Lei , Ling Xiang , Liu Wensheng , Das Gokul M. , Li Fengzhi 
Published: June 2012

Abstract
Survivin, a unique member of the inhibitor of apoptosis (IAP) family proteins, is highly expressed in cancers but undetectable in most normal adult tissue. Survivin shows both inhibition of apoptosis and promotion of cell division. It plays a central role in cancer cell signaling network. Recent studies indicate that survivin may also play an important role in G1/S transition during cell cycle regulation. However, the underlying mechanism is unclear. Furthermore, although upregulation of p21WAF1/CIP1 (p21) expression by p53 plays an important role in p53-mediated cell G1 arrests in response to various distressing stimuli, it is unknown whether survivin plays a role in the regulation of p21 expression. Here, we report that forced expression of survivin in p53-wild type MCF-7 breast cancer cells inhibits the expression of the cell cycle inhibitor p21 protein, mRNA and promoter activity, while the survivin C84A mutant and survivin antisense failed to do so. Cotransfection experiments in the p53 mutant H1650 lung cancer cell line showed that exogenous survivin expression neutralizes p53-induced p21 expression and promoter activity. Both p53 and survivin interacts on two p53 binding sites in the p21 promoter (−2313 to -2212; -1452 to -1310), and survivin protein physically interacts with p53 protein in cancer cells. Additionally, we identified a PKC phosphorylation site at T127 that plays a critical role in inhibition of p21 promoter activity by survivin. Together, we propose that survivin acts as a transcription factor or cofactor to interact with p53 on the p21 promoter leading to transcriptional inhibition of p21 expression at least in part by neutralizing p53-mediated transcriptional activation of the p21 gene.
*LT was a pre-doctoral Chinese fellowship student (Second West China Hospital, Sichuan University, Sichuan 610041, China) at the time this work was performed in the Li laboratory
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2178. doi:10.1158/1538-7445.AM2011-2178
Abstract 2179: Bile acids downregulate the squamous differentiation program of esophageal cells
Authors: Reveiller Marie , Ghatak Sayak , Kalatskaya Irina , Toia Liana , DSouza Mary , Zhou Zhongren , Bandla Santhoshi , Godfrey Tony E. , Peters Jeffrey 
Published: June 2012

Abstract
Background: The lumen of the normal esophagus is covered by a nonkeratinized, stratified squamous epithelium. However, in individuals with prolonged gastroesophageal reflux disease the squamous epithelium is gradually replaced by a more acid-resistant metaplastic columnar epithelium known as Barrett's Esophagus (BE). BE is the strongest known risk factor for development of esophageal adenocarcinoma. Understanding the molecular mechanisms underlying the formation of BE is fundamental to the development of new and effective prevention and treatment strategies for patients with BE.
Methods: We performed a global analysis of gene expression in normal squamous esophageal cells in response to bile acids or acid exposure. Differentially expressed genes were classified into major biological functions based on analysis using pathway and interaction network software programs. Array data were verified by quantitative PCR and western blot both in-vitro and in human biopsies from esophageal normal squamous and columnar epithelia.
Results: Bile acids modulated expression of 218 genes (153 up and 65 down) and acid 112 genes (31 up and 81 down). Interestingly, genes involved in squamous differentiation formed the largest functional group of differentially expressed genes and consisted of 40 genes downregulated by bile acids exposure. Bile acids decreased expression of key squamous differentiation genes such as KRT10, KRTDAP and GRHL1 which was confirmed at both the mRNA and protein level as was increased expression of CDX2, a transcription factor key to the intestinal epithelial phenotype. Bile acids induced expression changes were also seen in genes involved in the pathways of cell adhesion, DNA repair, oxidative stress, cell cycle, Wnt signaling and lipid metabolism. Expression of DSG1, a target gene of GRHL1, and DKK1, a Wnt inhibitor, were confirmed to be respectively downregulated and upregulated by bile acids. Further, expression data from human columnar epithelial biopsies revealed low or no expression of KRT10, KRTDAP, DSG1 and GRHL1 compared to squamous epithelia. Finally, network analysis suggested that bile acids exposure modulated the transcription activity of CREB and bile acids induced phosphorylation of CREB was confirmed experimentally.
Conclusion: We report for the first time that bile acids inhibit the squamous differentiation program of esophageal cells while inducing columnar differentiation via CDX2 expression possibly via CREB and Wnt signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2179. doi:10.1158/1538-7445.AM2011-2179
Abstract 2180: Antagonistic relationship between the tumor suppressor ING4 and estrogen signaling in breast cancer
Authors: Whitsett Timothy G. , Kim Suwon 
Published: June 2012

Abstract
ING4 is a tumor suppressor that plays a role in many cancer-related cellular processes, including cell proliferation, apoptosis, contact inhibition and cell migration. Our lab found ING4 is deleted in 15% of estrogen receptor (ER)-positive breast cancers, implicating a role for ING4 as a tumor suppressor in estrogen-driven breast cancer. Estrogen is a tumor promoter in breast cancer, causing cell proliferation, cell survival and cell migration. We hypothesize that estradiol (E2) exposure suppresses ING4, and conversely that the expression of ING4 modulates estrogen-induced phenotypes in breast cancer cells. We employed qPCR to test whether E2 suppressed ING4 in a time-, dose- and ER-dependent manner. By over-expressing or knocking down the expression of ING4 in MCF-7 breast cancer cells, we determined whether ING4 affected E2-induced cell proliferation. Physiological levels of E2 (100pM-10nM) suppressed the expression of ING4 in MCF-7 cells by more than 50% at early time points (6-24 hours). The suppression of ING4 by E2 was dependent on ER, as blocking ER with a pure anti-estrogen completely abrogated the suppression of ING4 by E2. Having shown that E2 suppressed ING4, we next tested whether the expression level of ING4 could affect E2-induced cell proliferation in breast cancer cells. The knockdown of ING4 by shRNA in MCF-7 cells resulted in a hyper-proliferation in response to E2 exposure. Conversely, the over-expression of ING4 in MCF-7 cells completely abolished the proliferative response to E2 seen in MCF-7 pMIG (vector alone) cells. In hormone-depleted media, MCF-7 cells over-expressing ING4 underwent apoptosis as demonstrated by the cleavage of caspase-7 and PARP. Estradiol exposure did not rescue the apoptotic phenotype. The over-expression of ING4 in MCF-7 cells suppressed the protein expression of Bcl-2, facilitating cell death. The suppression of Bcl-2 was necessary for cell death as the ectopic expression of Bcl-2 rescued the apoptotic phenotype induced by ING4 over-expression in hormone-depleted media. This work demonstrates an antagonistic relationship between E2 signaling and the tumor suppressor ING4 in breast cancer cells. The suppression of ING4 by E2 may indicate a novel mechanism of E2 action in breast cancer. This work also suggests that the expression of ING4 in estrogen-driven breast cancer may determine the magnitude of response to estrogen and anti-estrogen therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2180. doi:10.1158/1538-7445.AM2011-2180
Abstract 2183: Tumor suppressor LZAP regulates cell cycle progression and doming during zebrafish epiboly
Authors: Liu Dan , Yarbrough Wendell G. , Kanpik Ela W. , Wang Wen-Der 
Published: June 2012

Abstract
Initial stages of embryonic development rely on rapid, synchronized cell divisions of the fertilized egg followed by a set of morphogenetic movements collectively called epiboly and gastrulation. Lzap is a putative tumor suppressor whose expression is lost in 30% of head and neck squamous cell carcinomas. Lzap activities include regulation of cell cycle progression and response to therapeutic agents. Here we explore developmental roles of the lzap gene during zebrafish morphogenesis. Lzap is highly conserved among vertebrates and is maternally deposited. Expression is initially ubiquitous during gastrulation, and later becomes more prominent in the pharyngeal arches, digestive tract and brain. Antisense morpholino-mediated depletion of Lzap resulted in delayed cell divisions during blastomere formation, resulting in fewer, larger cells. Furthermore, the Lzap-deficient embryos failed to initiate epiboly – the earliest morphogenetic movement in animal development – which has been shown to be dependent on cell adhesion and migration of epithelial sheets. Our results strongly implicate Lzap in regulation of cell cycle progression, adhesion and migratory activity of epithelial cell sheets during early development. These functions provide further insight into Lzap activity that may contribute not only to development, but also to tumor formation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2183. doi:10.1158/1538-7445.AM2011-2183
Abstract 2199: SOX1 functions as a tumor suppressor through antagonizing WNT/β-catenin signaling pathway in hepatocellular carcinoma
Authors: Tsao Chun-Ming , Lin Wen-Chi , Yu Pei-Ning , Shih Yu-Lueng , Hsieh Tsai-Yuan , Hsieh Chung-Bao , Lai Hung-Cheng , Yan Ming-De , Lin Ya-Wen 
Published: June 2012

Abstract
Oncogenic activation of the Wnt/β-catenin signaling pathway is common in hepatocellular carcinoma (HCC). Aberrant hypermethylation of tumor suppressor genes in their promoter regions is frequently found in human cancers. Our previous works have demonstrated that SOX1 gene was hypermethylated in HCCs as well as cervical and ovarian cancers. A growing number of papers suggest that SOX family proteins, such as SOX9, SOX17, SOX4 and SOX2, serve as either tumor suppressors or oncoproteins through manipulating Wnt signaling pathway in different types of cancer. However the molecular mechanism is not well understood.
In this study, we established an inducible system to overexpress SOX1 in HCC cell lines and checked whether SOX1 have tumor suppressor function in vitro and in vivo. We found that overexpression of SOX1 could inhibit cell proliferation and colony formation in HCC cells and suppress tumor growth in xenograft mice. Next we used GST pull-down, co-immunoprecipitation (co-IP), immunocytochemistry and luciferase reporter assay to study whether SOX1 could interact with β-catenin to regulate Wnt/β-catenin signaling. Our data showed that SOX1 is physically associated with β-catenin/ TCF complex and could inhibit the TCF-dependent transcriptional activity. Furthermore, SOX1 was co-localized with β-catenin in nucleus by confocal microscopy. These results suggest that SOX1 functions as a tumor suppressor through interfering Wnt/β-catenin signaling in HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2199. doi:10.1158/1538-7445.AM2011-2199
Abstract 2219: Inhibitor of differentiation-1 is a novel prognostic factor among NSCLC patients with adenocarcinoma histology and contributes to therapy resistance
Authors: Ponz-Sarvise Mariano , Nguewa Paul A. , Pajares Maria J. , Agorreta Jackeline , Lozano Maria D. , Redrado Miriam , Pio Ruben , Behrens Carmen , Wistuba Ignacio , Garcia-Foncillas Jesus , Montuenga Luis M. , Calvo Alfonso , Gil-Bazo Ignacio 
Published: June 2012

Abstract
High Id1 levels have been found in some tumor types, particularly in advance stages. We aimed to study Id1 levels and their prognostic value in a large series of different histologies of stage I-IV NSCLC patients and to test Id1 function in cell lines and cells derived from malignant pleural effusions (MPE) from patients (pts). Id1 expression was analyzed in NSCLC samples from 311 pts and 65 normal lung tissues by immunohistochemistry. Id1 mRNA expression was also studied in 111 pts using publicly available microarrays. Significantly higher Id1 protein expression levels were found in tumors compared to normal tissue (p&lt;0.001) and in adenocarcinomas (AC) compared so squamous histology (p&lt;0.001). Among the localized NSCLC pts undergoing surgery, higher Id1 expression levels were associated with a shorter overall survival (OS) for AC histology (p=0.017). In the surgery+adjuvant chemo-radiotherapy pts, the same correlation was found between Id1 levels and OS among AC samples (p=0.038). Consistently, in stage IV pts receiving palliative chemotherapy, Id1 maintained its prognostic value (shorter OS in pts with higher levels) for AC (p=0.003). Id1 was also correlated with time-to-progression (TTP) after chemotherapy (lower levels, prolonged TTP) in AC pts (p=0.008). The in silico analysis confirmed this association. High expression of Id1 was also found by western blots in squamous cell lines (H520, HCC15, H157 and H58) and in lesser extent in AC cell lines (SKLU-1, LXF-289, H322, H23) and MPE-derived AC cells. Id1 knockdown resulted in a significant reduction of the clonogenic activity of squamous and AC cells. Id1 silencing on radiotherapy and chemotherapy-resistant MPE-derived cells restored sensitivity to both therapies. We conclude that Id1 protein and mRNA expression is an independent prognostic factor among pts with AC but no other histologies, regardless of the stage or treatment received. In cell lines derived from MPE pts, Id1 downregulation decreases NSCLC cell proliferation and sensitizes cells to radiotherapy and chemotherapy, in vitro.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2219. doi:10.1158/1538-7445.AM2011-2219
Abstract 2222: Identify and evaluate novel biomarker CIP2A for cervical cancer diagnostics
Authors: Huang Lisa P. , Libby Erika , Trama Jason 
Published: June 2012

Abstract
Early detection of cervical cancer is critical for a favorable prognosis. HPV infection is not a reliable marker for predicting the malignancy potential of cervical lesions. Standard cytological detection methods such as Pap smear are highly subjective. As a result, there remains a very high demand for a diagnostic assay capable of determining which early stage cervical lesions will progress to cervical cancer. We sought to identify cervical cancer biomarkers and to test the hypothesis that the small percentage of HPV positive patients who progress to cervical cancer have aberrant expression of the cell signaling component, c-myc and its regulators, including protein phosphatase 2A (PP2A) and cancerous inhibitor of PP2A (CIP2A).
In this study, Bio-Plex liquid microarray analysis was used to determine the HPV status cervical specimens (NNon-tumor=28, NTumor=30). qRT-PCR, Western blotting, flow cytometry, and ELISA analysis were used to access expression levels of CIP2A, c-myc, PP2A, Ki67, TOP2A, MCM2, MCM5, p14ARF, and p16INK4a.
Our studies indicate CIP2A was abundantly expressed in cervical cancer cell lines and it was not expressed in normal epithelial cells. CIP2A mRNA levels were higher in cervical tissues from stage I, II, and III cervical cancer patients in comparison to the level of CIP2A mRNA in normal tissue. CIP2A protein was specifically expressed in cervical cancer tissues at different cancer stages, and not in non-cancer or adjacent non-tumor cervical tissue. Our data showed that CIP2A mRNA detection had a sensitivity of 80% and specificity of 91% and CIP2A protein expression detection had a sensitivity of 80% and specificity of 100%, similar to that of p16INK4a biomarker. Although CIP2A/PP2A/c-myc pathway may work together in the development of cervical cancer, our data strongly indicate that only CIP2A (but not PP2A or c-myc) is a reliable biomarker for detection of cervical cancer. In this study, we also examined the combined use of at least two biomarkers as a tool to detect cervical cancer. Our studies also suggest there was no strong correlation of CIP2A expression with HPV subtype, age, ethnical background, or other patient characteristics.
In conclusion, our clinical studies suggest that CIP2A is a reliable and sensitive biomarker for detection of cervical cancer. CIP2A mRNA or protein can both serve as reliable markers. A combined use of CIP2A with at least on additional marker selected from the group consisting of Ki67, TOP2A, MCM2, MCM5, and p16 will improve the assay sensitivity and specificity. CIP2A is a novel biomarker for early detection of cervical cancer in humans.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2222. doi:10.1158/1538-7445.AM2011-2222