ROLE OF ETHANOL IN HEPATOCELLULAR CARCINOMA PROGRESSION

申请人摘要： 长期饮酒被认为是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，最明显的是肝炎、吸烟和/或贫穷 饮食，使人们很难确定酒精 影响肝细胞癌的发展和/或进展。我们之前的报道 实验室证实抑制性鸟嘌呤的表达和功能增加 超过80%的人肝细胞癌标本中的核苷酸蛋白(GI-蛋白) 与正常相比，配对的肝脏样本。此外，刺激 肝细胞癌中的GI蛋白通过丝裂原激活蛋白促进细胞有丝分裂 在肝细胞癌中，丝裂原活化蛋白激酶(MAPK)级联，这一效应在正常肝细胞中没有观察到。 在长期接触乙醇后，我们最近报告了选择性升高 肝细胞癌与正常对照中Gi蛋白依赖的有丝分裂的调节 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“增加的细胞有丝分裂 肝细胞癌的特征至少部分依赖于胃肠道蛋白的调节 MAPK的活性。此外，我们假设“长期接触 与乙醇相比，乙醇在肝细胞癌中选择性地上调这些通路 正常的肝细胞，在这样做的过程中，加速肿瘤的生长。 探索性/发展性赠款将决定 乙醇对血管紧张素转换酶特定成分表达和功能的影响 GI蛋白依赖的MAPK信号在肝细胞癌中的级联作用。利用体外培养的人和 伴有正常静止期和增殖期的肝癌动物模型 肝细胞，我们将定义：(I)特定成分的作用 Gi-Protein-MAPK信号转导通路在调节正常和正常细胞增殖中的作用 转化(肝细胞癌)肝细胞，以及(Ii)剂量和时间效应 乙醇和乙醇代谢产物对Gi-2表达和功能的影响 正常肝细胞和转化肝细胞中的蛋白-MAPK信号通路。我们 预计这些研究将提供对 了解乙醇如何调节信号转导/生长调节 对正常和转化的细胞功能和有丝分裂至关重要的途径。我们 相信在细胞层面上对肝细胞癌病因的理解 水平对体内研究的未来发展至关重要，这种研究允许 对肝细胞癌有更清晰的临床认识，以及 为这一致命疾病的治疗干预开发替代疗法 恶毒。

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.