Molecular mechanism of alcohol-associated liver tumor development

摘要 描述酒精性肝损伤的分子机制及其发病风险 肝细胞癌对于酒精性肝病的研究具有重要价值。我们 首次证实酒精可增加Brf1(TFIIIB相关因子1)的表达和Pol III基因 (RNA聚合酶III依赖的基因)转录在细胞培养模型中。这种诱导也发生在 酒精喂养野生型(WT)小鼠。Brf1表达增加和Pol III基因转录促进肝肿瘤 酒精喂养的NS5A(丙型肝炎病毒非结构5A蛋白)转基因小鼠的形成，而不是饲料喂养的对照小鼠 NS5A小鼠。我们的初步研究表明，Brf1在人类肝细胞癌中高度表达。高 Brf1在人肝细胞癌中的表达显示其存活时间较短。进一步分析表明，Brf1和Pol III 在饮酒者肝细胞癌中，基因转录增强。我们最近的研究表明， 酒精激活MSK1(有丝分裂原和应激活化蛋白激酶1)，介导细胞转化 以及在其他癌症模型中的肿瘤形成。鉴于这一令人信服的证据，我们提出了一个假设 乙醇激活JNK1，JNK1介导MSK1活性调节Brf1表达和Pol III基因 转录，从而促进酒精性肝病和肝肿瘤的发展。使用单元格 培养模型和动物模型，我们将确定MSK1和Brf1作为关键因素在 酒精诱导的反应。这些研究将使我们能够探索酒精的分子机制- 相关肝病和肝细胞癌。我们将探讨以下目标： 目的1.检测酒精诱导POL III基因失控的信号事件； 目的2.研究酒精对BRF1基因表达的调控作用； 目的3.检测BRF1降低是否抑制酒精诱导的肝肿瘤形成。 这些提出的目标的成功完成应该会极大地提高我们对分子 酒精相关性肝癌的发病机制。对Brf1和Pol III基因表达的抑制作用 MSK1 KO小鼠和他莫昔芬诱导的条件性Brf1 KO小鼠应能抑制肝癌 队形。因此，拟议项目的结果可能为治疗提供一种潜在的策略 得了肝癌。

ABSTRACT Characterizing the molecular mechanisms that underlie alcohol-induced liver injury and the risk of hepatocellular carcinoma (HCC) is immensely valuable for the study of alcoholic liver diseases (ALDs). We demonstrated, for the first time, that alcohol increases Brf1 (TFIIIB-related factor 1) expression and Pol III gene (RNA polymerase III-dependent gene) transcription in cell culture models. This induction occurs as well in alcohol-fed wild type (WT) mice. Increased Brf1 expression and Pol III gene transcription promote liver tumor formation in alcohol-fed NS5A (HCV non-structural 5A protein) transgenic mice, but not in control diet-fed NS5A mice. Our preliminary studies have revealed that Brf1 is highly expressed in human HCC cases. High expression of Brf1 in human HCC displays a short survival time. Further analysis indicates that Brf1 and Pol III gene transcription are enhanced in the cases of Alcohol-drinker HCC. Our recent studies have indicated that alcohol activates MSK1 (mitogen- and stress-activated protein kinase 1), which mediates cell transformation and tumor formation in other cancer models. Given this compelling evidence, we propose a hypothesis that ethanol activates JNK1, which mediates MSK1 activity to modulates Brf1 expression and Pol III gene transcription, thereby contributing to alcoholic liver disease and liver tumor development. Using cell culture models and animal models, we will determine the roles of MSK1 and Brf1 as crucial factors in the alcohol-induced response. These studies will allow us to explore the molecular mechanism of alcohol- associated liver diseases and HCC. The following aims will be explored: AIM 1. TO TEST SIGNALING EVENTS OF ALCOHOL-INDUCED DEREGULATION OF POL III GENES; AIM 2. TO DETERMINE HOW ALCOHOL-INDUCED BRF1 EXPRESSION IS MODULATED; AIM 3. TO TEST IF BRF1 REDUCTION REPRESSES ALCOHOL-PROMOTED LIVER TUMOR FORMATION. Successful completion of these proposed aims should greatly enhance our understanding of molecular mechanism of alcohol-associated liver cancer. The inhibition of Brf1 and Pol III gene expression by using MSK1 KO mice and tamoxifen inducible conditional Brf1 KO mice should result in a repression of liver tumor formation. Therefore, the results from the proposed project could provide a potential strategy for the treatment of liver cancer.