Beta-Catenin Signaling in HBxAg Mediated HCC.

HBxAg 介导的 HCC 中的 β-连环蛋白信号传导。

• 批准号: 7339815
• 负责人: MARK A FEITELSON
• 金额: $ 25.67万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-06 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339815
• 关键词: Address; Adenoviruses; Agar; Alleles; Anchorage-Independent Growth; Antigens; Apoptosis; Biological Assay; Bromodeoxyuridine; Cell Cycle; Cell Line; Cells; Chemoprevention; Chronic; Critical Pathways; DNA biosynthesis; Data; Development; Down-Regulation; E-Cadherin; Epithelial; Exons; Figs - dietary; Flow Cytometry; Gene Targeting; Genes; Glycogen Synthase Kinases; Growth; Half-Life; Harvest; Health Benefit; Hepatitis B Virus; Hepatitis B X-Protein; Hepatoblastoma; Hepatocarcinogenesis; Hepatocyte; Human; In Situ Nick-End Labeling; Individual; Liver; Liver diseases; Liver neoplasms; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Microarray Analysis; Molecular; Mus; Nuclear; Nude Mice; Partner in relationship; Pathogenesis; Patients; Pharmaceutical Preparations; Phosphotransferases; Primary carcinoma of the liver cells; Property; Proteins; Public Health; Recombinants; Research; Research Personnel; Run-On Assays; Serum; Signal Pathway; Signal Transduction; Staining method; Stains; Testing; Therapeutic Intervention; Time; Transgenic Mice; Treatment outcome; Up-Regulation; Western Blotting; Work; base; beta catenin; depressed; in vivo; inhibitor/antagonist; mRNA Stability; multicatalytic endopeptidase complex; mutant; offspring; promoter; recombinase; research study; therapeutic target; tumor; tumorigenesis; vector

Hepatitis B virus (HBV) encoded x antigen (HBxAg) is a /raws-activating protein that contributes to the development of hepatocellular carcinoma (HCC) by the up- or down-regulated expression of selected hepatocellular genes. To identify some of these genes, HBxAg or vector were introduced into the human hepatoblastoma cell line, HepG2. Differentially expressed genes were identified by microarray analysis and by PowerBlot (SDS/PAGE followed by western blotting). Both assays showed decreased E-cadherin and increased expression of p-catenin and several p-catenin target genes in HBxAg [+] compared to [-] cells. In the livers of HBV carriers, there was an inverse relationship between HBxAg staining and E-cadherin and co- staining between HBxAg and p-catenin, suggesting that HBxAg contributes to hepatocellular transformation by altering the P-catenin signaling pathway. Hence, the objective of this work is to elucidate the mechanisms whereby HBxAg stabilizes p-catenin and thereby stimulates signaling, and to determine the contribution of these mechanisms to HBxAg mediated transformation. Accordingly, experiments will test the hypothesis that the accumulation/activation of p-catenin in HBxAg positive cells results from HBxAg /r<ms-activationof the P-catenin gene, from HBxAg inactivation of glycogen synthase kinase 3p (GSKSp), from the HBxAg down- regulation of E-cadherin, and/or from the HBxAg inhibition of p-catenin degradation in the proteasome (aim 1). Additional experiments will test whether the HBxAg stabilization of p-catenin contributes to the pathogenesis of HCC (aim 2). These experiments will establish the extent to which up-regulated p-catenin signaling underlies the pleiotropic properties whereby HBxAg contributes to HCC development on the molecular level, and the corresponding mechanism(s) whereby this occurs. Given that wild type P-catenin is up-regulated in the majority of HBV associated HCCs, elucidation of the underlying mechanism(s) will identify critical pathways that will be targeted for chemoprevention of HCC and for therapeutic intervention in tumor bearing patients. The results from this research would also provide therapeutic targets for the application of existing drugs (against p-catenin effectors) in patients with HCC. In doing so, the proposed work is expected to promote the development of multiple public health benefits for HBV infected carriers with chronic liver disease and HCC.

乙型肝炎病毒（HBV）编码的x抗原（HBxAg）是一种/raws激活蛋白，有助于