ROLE OF ETHANOL IN HEPATOCELLULAR CARCINOMA PROGRESSION

乙醇在肝细胞癌进展中的作用

• 批准号: 6327287
• 负责人: IAIN HUGH MCKILLOP
• 金额: $ 15.95万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327287
• 关键词: biological signal transduction; cell growth regulation; cell line; cell proliferation; cell transformation; dosage; drug metabolism; enzyme activity; enzyme inhibitors; enzyme mechanism; ethanol; flow cytometry; gene expression; guanine nucleotide binding protein; hepatocellular carcinoma; laboratory rat; liver cells; male; mitogen activated protein kinase; neoplastic growth; northern blottings; pathologic process; protein structure function; tissue /cell culture; toxicology; western blottings

APPLICANT'S ABSTRACT: Chronic alcohol consumption is considered a major pathogenic factor in the development of hepatocellular carcinoma (HCC). However, the presence of other factors in the alcoholic patient, most notably hepatitis, smoking and/or poor diet, make it difficult to determine the precise mechanisms whereby alcohol affects the development and/or progression of HCC. Previous reports from our laboratory demonstrate increased expression and function of inhibitory guanine nucleotide proteins (Gi-proteins) in more than 80% of human HCC specimens when compared to normal, pair matched liver specimens. Furthermore stimulation of Gi- proteins in HCC increases cell mitogenesis via a mitogen activated protein kinase (MAPK) cascade in HCC, an effect not observed in normal hepatocytes. Following chronic exposure to ethanol we have recently reported selective up regulation of Gi-protein dependent mitogenesis in HCC versus normal, non-neoplastic hepatocytes Based on these observations and current literature, our central hypothesis is that " The increased cellular mitogenesis characteristic of HCC is dependent, at least in part, on Gi-protein regulation of MAPK activity. Furthermore, we hypothesize that "chronic exposure to ethanol acts to selectively up regulate these pathways in HCC as compared to normal hepatocytes and, in doing so, accelerates tumor growth." This NIAAA exploratory/developmental grant will determine the effects of ethanol on changes in expression and function of specific components of Gi-protein-MAPK dependent signaling cascades in HCC. Using in vitro human and animal models of HCC in conjunction with normal quiescent and proliferating hepatocytes, we will define: (i) the roles of specific components of Gi-protein-MAPK signaling in regulating cell proliferation in normal and transformed (HCC) hepatocytes, and (ii) the dose and temporal effects of ethanol and ethanol metabolites on the expression and function of Gi- protein-MAPK signaling pathways in normal and transformed hepatocytes. We anticipate these studies will provide a critical insight into the understanding of how ethanol regulates a signal transduction/growth regulatory pathway essential to normal and transformed cell function and mitogenesis. We believe this level of understanding of the etiology of HCC at the cellular level is critical to the future development of in vivo studies that allow a clearer, clinical understanding of HCC, as well as the potential for developing alternative treatments for therapeutic intervention in this lethal malignancy.

申请人摘要： 慢性酒精消费被认为是一个主要的致病因素， 肝细胞癌（HCC）的发展。然而，其他人的存在 酒精患者的因素，最明显的是肝炎，吸烟和/或贫穷 饮食，使其难以确定酒精的确切机制， 影响HCC的发展和/或进展。以前的报告从我们的 实验室证明抑制性鸟嘌呤表达和功能增加 在超过80%的人HCC标本中， 与正常配对的肝脏标本进行比较。此外，刺激 肝细胞癌中的Gi蛋白通过促分裂原活化蛋白增加细胞有丝分裂 在HCC中的MAPK级联，在正常肝细胞中没有观察到的效果。 在长期暴露于乙醇后，我们最近报道了选择性升高 与正常相比，HCC中Gi蛋白依赖性有丝分裂发生的调节， 非肿瘤性肝细胞基于这些观察和当前文献， 我们的中心假设是“细胞有丝分裂的增加 HCC的特征至少部分依赖于Gi蛋白的调节 MAPK活性。此外，我们假设“长期暴露于 乙醇在HCC中起选择性上调这些途径的作用， 正常的肝细胞，并在这样做时加速肿瘤生长。“这个NIAAA 探索性/发展性赠款将决定 乙醇对特定成分表达和功能的影响 HCC中的Gi蛋白-MAPK依赖性信号级联。使用体外人和 HCC与正常静止期和增殖期结合的动物模型 肝细胞，我们将定义：（一）特定成分的作用， Gi-protein-MAPK信号通路在调节正常和非正常细胞增殖中的作用 转化（HCC）肝细胞，和（ii）剂量和时间效应 乙醇及乙醇代谢产物对GI-的表达和功能的影响 正常和转化肝细胞中的蛋白质-MAPK信号通路。我们 预计这些研究将提供一个关键的洞察力， 了解乙醇如何调节信号转导/生长调节 正常和转化细胞功能和有丝分裂所必需的途径。我们 我相信这种水平的理解肝癌的病因在细胞 水平是至关重要的未来发展的体内研究，允许 对HCC的临床认识更加清晰， 开发替代疗法，用于治疗这种致命的 恶性肿瘤