ROLE OF ETHANOL IN HEPATOCELLULAR CARCINOMA PROGRESSION

乙醇在肝细胞癌进展中的作用

• 批准号: 6509393
• 负责人: IAIN HUGH MCKILLOP
• 金额: $ 5.35万
• 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 2002-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6509393
• 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： 长期饮酒被认为是导致糖尿病的主要致病因素。 肝细胞癌（HCC）的发展。然而，其他人的存在 酗酒患者的因素，最显着的是肝炎、吸烟和/或贫困 饮食，使得很难确定酒精的精确机制 影响 HCC 的发生和/或进展。我们之前的报道 实验室证明抑制性鸟嘌呤的表达和功能增加 超过 80% 的人类 HCC 样本中含有核苷酸蛋白（Gi 蛋白） 与正常的、配对的肝脏标本相比。此外刺激 HCC 中的 Gi 蛋白通过有丝分裂原激活蛋白增加细胞有丝分裂 HCC 中的激酶 (MAPK) 级联反应，在正常肝细胞中未观察到这种效应。 在长期接触乙醇后，我们最近报告了选择性上升 HCC 与正常情况下 Gi 蛋白依赖性有丝分裂的调节 非肿瘤性肝细胞 根据这些观察结果和现有文献， 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 蛋白调节 MAPK 活性。此外，我们假设“长期暴露于 与相比，乙醇选择性上调 HCC 中的这些途径 正常肝细胞，从而加速肿瘤生长。”NIAAA 探索性/发展性资助将决定以下方面的影响 乙醇对特定成分表达和功能变化的影响 HCC 中的 Gi-蛋白-MAPK 依赖性信号级联。使用体外人类和 与正常静止期和增殖期相结合的 HCC 动物模型 肝细胞，我们将定义：（i）特定成分的作用 Gi-蛋白-MAPK信号传导在正常和正常细胞增殖中的调节作用 转化（HCC）肝细胞，以及（ii）剂量和时间效应 乙醇和乙醇代谢物对 Gi- 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 预计这些研究将为我们提供重要的见解 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 相信对 HCC 病因学的细胞水平的了解 水平对于体内研究的未来发展至关重要，这些研究允许 对 HCC 的更清晰的临床了解以及潜在的 开发替代疗法以治疗干预这一致命疾病 恶性肿瘤。