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: 7536277
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536277
• 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; DNA chemical synthesis; 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; Transcriptional Activation; Transgenic Mice; Treatment outcome; Up-Regulation; Western Blotting; Work; base; beta catenin; in vivo; inhibitor/antagonist; mRNA Stability; multicatalytic endopeptidase complex; mutant; 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(HBVx)编码的x抗原(HBxAg)是一种/RAWS激活蛋白，它有助于 SELECT基因表达上调或下调与肝细胞癌的发生 肝细胞基因。为了识别其中的一些基因，将HBxAg或载体导入人类 肝母细胞瘤细胞系HepG2。差异表达基因通过微阵列分析和 PowerBlot(SDS/PAGE和Western blotting)。两种检测方法都显示E-钙粘素和 与[-]细胞相比，p-catenin和几个p-catenin靶基因在HBxAg[+]中的表达增加。在……里面 在乙肝病毒携带者的肝组织中，HBxAg染色与E-钙粘附素、辅助性粘附素的表达呈负相关。 HBxAg和p-catenin之间的染色，提示HBxAg参与了肝细胞转化 通过改变P-连环蛋白信号通路。因此，这项工作的目的是阐明其作用机制 通过HBxAg稳定p-连环蛋白从而刺激信号转导，并确定 这些机制对HBxAg介导的转化具有重要意义。因此，实验将检验这一假设 HBxAg阳性细胞中p-catenin的积聚/激活是HBxAg/r&lt；ms激活的结果。 P-连环蛋白基因，从HBxAg失活的糖原合成酶激酶3p(GSKSp)，从HBxAg向下- E-钙粘蛋白和/或HBxAg抑制蛋白酶体中p-连环蛋白降解的调节(目的 1)。更多的实验将测试p-catenin的HBxAg稳定性是否有助于 肝癌的发病机制(目标2)。这些实验将确定上调p-连锁素的程度 信号转导是HBxAg促进肝细胞癌发生的多效性基础。 分子水平，以及相应的发生机制(S)。鉴于野生型P-连环蛋白是 在大多数乙肝病毒相关的肝癌中上调，阐明其潜在机制(S) 确定针对肝细胞癌的化学预防和治疗干预的关键途径 在有肿瘤的病人身上。这项研究的结果也将为 现有药物(针对p-连环蛋白效应物)在肝癌患者中的应用。在此过程中，建议的 预计将努力促进为乙肝病毒感染携带者提供多种公共健康益处 患有慢性肝病和肝细胞癌。