Analysis of a novel regulator of hepatocellular carcinoma

一种新型肝细胞癌调节因子的分析

基本信息

批准号：
8215770
负责人：
DEVANAND SARKAR
金额：
$ 30.09万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215770
关键词：
Adherence Agar Alcoholism Anchorage-Independent Growth Animals Apoptosis Asians Astrocytes Blood Vessels Breast Cancer Cell CREB-binding protein Cell Nucleus Cell Survival Cell surface Cells Chronic Chronic Hepatitis C Cirrhosis Co-Immunoprecipitations Complex Correlation Studies Country DNA Binding Domain Data Development Diagnosis Diagnostic Diethylnitrosamine Disease Endothelium Excision Gene Expression Gene Silencing Genes Genetic Transcription Growth Ha-ras Genes Hepatitis B Virus Hepatitis C Hepatitis C virus Hepatocarcinogenesis Hepatocyte High Prevalence Human IL8 gene Incidence Individual Inflammatory Knowledge Liver Lung MEKs Malignant Epithelial Cell Malignant Glioma Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Mediating Messenger RNA Micrococcal Nuclease Molecular Monitor Neoplasm Metastasis Normal Cell Nuclear Nuclear Proteins Nude Mice Operative Surgical Procedures Pathogenesis Pathway interactions Patients Play Primary carcinoma of the liver cells Process Prognostic Marker Proteins RNA Interference RNA Splicing RNA-Induced Silencing Complex Radioimmunoconjugate Recurrence Regimen Resistance Role Sampling Serum Signal Pathway Signal Transduction Signal Transduction Pathway Small Interfering RNA Staging Staining method Stains Starvation Systemic Therapy TNF gene Testing Therapeutic Tissue Microarray Transcriptional Regulation Transgenic Animals Transgenic Mice Translating Treatment Efficacy Two-Hybrid System Techniques Virus Diseases Yeasts angiogenesis base c-myc Genes cancer cell chemotherapy chromatin immunoprecipitation cytokine disease phenotype effective therapy fetal human CREBBP protein in vivo Model insight mRNA Precursor mRNA Stability malignant breast neoplasm matrigel melanocyte melanoma mouse model novel novel therapeutics outcome forecast overexpression p65 promoter public health relevance rapid growth research study senescence tool tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a highly aggressive cancer with no currently available effective treatment. Understanding the molecular mechanism of HCC development and progression is imperative to develop novel, effective and targeted therapies for this lethal disease. Our recent findings reveal that Astrocyte Elevated Gene-1 (AEG-1) plays an important role in HCC pathogenesis. In human HCC samples AEG-1 mRNA and protein were significantly overexpressed compared to normal liver and in a subset of HCC patients AEG-1 gene itself was amplified. In 109 HCC patients, AEG-1 protein was overexpressed in >90% cases and AEG-1 expression level showed significant correlation with the stages and grades of the disease. Forced overexpression of AEG-1 in less aggressive HCC cells resulted in highly aggressive, angiogenic and metastatic tumors in nude mice. Conversely, inhibition of AEG-1 significantly abrogated growth of highly aggressive HCC cells in nude mice. In HCC cells, AEG-1 activated pro-survival signaling pathways such as MEK/ERK, PI3K/Akt, NF-?B and Wnt signaling pathways that are known to contribute to hepatocarcinogenesis and AEG-1 modulated specific genes regulating invasion, angiogenesis, chemoresistance and senescence. Additionally, AEG-1 protected primary human hepatocytes from induction of senescence. These findings strongly indicate that AEG-1 plays an important role in regulating HCC development and progression. AEG-1 is located both on the cell surface and in intracellular compartments including the nucleus. While the cell surface located AEG-1 facilitates metastasis by adhering to the endothelium, our findings indicate that the intracellular AEG-1 might contribute to the initial steps of tumorigenesis, such as immortalization and transformation, by turning on pro-survival signals and modulating gene expression. We have previously shown that AEG-1 functions as a transcriptional co-activator and presently we identify as an AEG-1 interacting partner Staphylococcal Nuclease Domain Containing-1 (SND1) which regulates gene expression by modulating transcription, mRNA splicing, RNA interference and mRNA stability. The long-term objectives of the present proposal are to identify key players regulating HCC pathogenesis and translate that knowledge for developing novel and effective targeted therapies. The immediate objectives of the present proposal are to analyze the role of AEG-1 in hepatocarcinogenesis in a transgenic mouse model; elucidate the role of AEG-1-SND1 interaction in mediating AEG-1 function as well as hepatocarcinogenesis; and establish AEG-1 as a diagnostic and prognostic marker for HCC by analyzing patient-derived HCC samples. Successful completion of the proposed studies will provide in-depth insights into structural and functional realms of AEG-1 thus facilitating development of strategies to block AEG-1 as a potential therapeutic regimen for HCC. PUBLIC HEALTH RELEVANCE: Astrocyte elevated gene-1 (AEG-1) is overexpressed in hepatocellular carcinoma (HCC) patients and plays a key role in regulating hepatocarcinogenesis by turning on pro- survival signals and modulating global gene expression. The proposed studies aim at understanding AEG-1 function by using a transgenic mouse model and analyzing AEG-1 interacting proteins and establishing AEG-1 as a diagnostic and prognostic marker for HCC.

描述（由申请人提供）：肝细胞癌（HCC）是一种高度侵略性的癌症，目前没有有效的治疗方法。了解HCC发育和进展的分子机制必须为这种致命疾病开发新颖，有效和有针对性的疗法。我们最近的发现表明，星形胶质细胞升高基因1（AEG-1）在HCC发病机理中起重要作用。在人类HCC样品中，与正常肝脏相比，AEG-1 mRNA和蛋白质明显过表达，在HCC患者的一部分中，AEG-1基因本身被放大。在109例HCC患者中，AEG-1蛋白在> 90％的病例中过表达，AEG-1表达水平与疾病的阶段和成绩显着相关。在不太侵略性的HCC细胞中强迫AEG-1的过度表达导致裸鼠高度攻击性，血管生成和转移性肿瘤。相反，对AEG-1的抑制显着消除了裸鼠高度攻击性HCC细胞的生长。在HCC细胞中，AEG-1激活了临床信号传导途径，例如MEK/ERK，PI3K/AKT，NF-？B和WNT信号传导途径，这些信号传导途径可有助于肝癌发生和AEG-1调节的特定基因，从而调节了入侵，血管生成，化学，化学，化学，化学，化学抗性和消毒。此外，AEG-1保护的原代人肝细胞免受衰老的诱导。这些发现强烈表明AEG-1在调节HCC的发展和进展中起着重要作用。 AEG-1既位于细胞表面，也位于包括细胞核在内的细胞内室中。虽然位于AEG-1的细胞表面通过粘附在内皮上促进转移，但我们的发现表明细胞内AEG-1可能会导致肿瘤发生的初始步骤，例如永生化和转化，例如，通过促进性卵巢溶性信号和调节基因表达。我们先前已经表明，AEG-1充当转录共激活因子，目前我们确定为AEG-1相互作用的伴侣葡萄球菌核酸酶结构域含有1（SND1），该结构域（SND1）通过调节转录，mRNA剪接，RNA，RNA，RNA干扰和mRNA稳定性来调节基因表达。本提案的长期目标是确定调节HCC发病机理的关键参与者，并将这些知识转化为开发新颖有效的有针对性疗法。本提案的直接目的是分析AEG-1在转基因小鼠模型中的作用。阐明AEG-1-SND1相互作用在介导AEG-1功能以及肝癌发生中的作用；并通过分析患者衍生的HCC样品来建立AEG-1作为HCC的诊断和预后标记。成功完成拟议的研究将为AEG-1的结构和功能领域提供深入的见解，从而促进制定阻止AEG-1作为HCC的潜在治疗方案的策略。公共卫生相关性：星形胶质细胞升高的基因-1（AEG-1）在肝细胞癌（HCC）患者中过表达，并通过打开促生存信号和调节全球基因表达来调节肝癌的作用在调节肝癌的作用中起关键作用。提出的研究旨在通过使用转基因小鼠模型并分析AEG-1相互作用蛋白并将AEG-1作为HCC的诊断和预后标记来理解AEG-1功能。