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: 7758228
• 负责人: MARK A FEITELSON
• 金额: $ 25.85万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758228
• 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; Depressed mood; 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; 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.

B型肝炎病毒（HBV）编码的X抗原（HBxAg）是一种激活蛋白，其有助于 肝细胞癌（HCC）的发展通过选择的 肝细胞基因为了鉴定这些基因中的一些，将HBxAg或载体引入人中， 肝母细胞瘤细胞系HepG 2。通过微阵列分析鉴定差异表达的基因， 通过PowerBlot（SDS/PAGE，然后是蛋白质印迹法）。两种检测均显示E-钙粘蛋白降低， 与[-]细胞相比，HBxAg [+]中β-连环蛋白和几种β-连环蛋白靶基因的表达增加。在 在HBV携带者的肝脏中，HBxAg染色与E-cadherin和co-cadherin呈负相关， HBxAg和β-连环蛋白之间的染色，表明HBxAg有助于肝细胞转化 通过改变β-连环蛋白信号通路。因此，这项工作的目标是阐明机制 从而HBxAg稳定β-连环蛋白，从而刺激信号传导，并确定 这些机制对HBxAg介导的转化。因此，实验将检验以下假设： β-连环蛋白在HBxAg阳性细胞中的积累/激活是由HBxAg /r<ms-激活 β-连环蛋白基因，从HBxAg灭活糖原合成酶激酶3 p（GSKSp），从HBxAg下调- 调节E-钙粘蛋白，和/或来自HBxAg抑制蛋白酶体中的β-连环蛋白降解（目的 1）。另外的实验将测试β-连环蛋白的HBxAg稳定化是否有助于HBxAg的表达。 HCC的发病机制（目的2）。这些实验将确定上调的β-连环蛋白 信号转导是多效性的基础，HBxAg在肝细胞上促进HCC的发展。 分子水平，以及由此发生的相应机制。鉴于野生型β-连环蛋白是 在大多数HBV相关HCC中上调，阐明其潜在机制将 确定HCC化学预防和治疗干预的关键途径 在肿瘤患者中。这项研究的结果也将为癌症提供治疗靶点。 现有药物（针对β-连环蛋白效应物）在HCC患者中的应用。在这样做时，拟议的 这项工作有望促进HBV感染携带者的多种公共卫生福利的发展 患有慢性肝病和肝癌