Molecular mechanism of alcohol-associated liver tumor development

摘要 描述酒精性肝损伤的分子机制和 肝细胞癌（HCC）对酒精性肝病（ALDs）的研究具有重要价值。我们 首次证明，酒精增加Brf 1（TFIIIB相关因子1）表达和Pol III基因表达。 (RNA聚合酶III依赖性基因）转录。这种诱导也发生在 酒精喂养的野生型（WT）小鼠。Brf 1表达增加和Pol III基因转录促进肝肿瘤的发生 在酒精喂养的NS 5A（HCV非结构5A蛋白）转基因小鼠中形成，但在对照饮食喂养的 NS 5A小鼠。我们的初步研究表明，Brf 1在人类HCC病例中高度表达。高 Brf 1在人HCC中的表达显示出短的存活时间。进一步的分析表明，Brf 1和Pol III 基因转录在饮酒者HCC中增强。我们最近的研究表明， 酒精激活介导细胞转化的MSK 1（促分裂原和应激激活蛋白激酶1） 和其他癌症模型中的肿瘤形成。鉴于这一令人信服的证据，我们提出一个假设， 乙醇激活JNK 1，JNK 1介导MSK 1活性以调节Brf 1表达和Pol III基因 转录，从而有助于酒精性肝病和肝肿瘤的发展。使用细胞 我们将通过对培养模型和动物模型的研究，确定MSK 1和Brf 1作为关键因素在细胞凋亡中的作用。 酒精引起的反应。这些研究将使我们能够探索酒精的分子机制- 相关肝病和HCC。将探讨以下目标： AIM 1.检测酒精诱导的POL III基因失调的信号事件; AIM 2.确定酒精诱导的BRF 1表达是如何调节的; AIM 3.测试BRF 1减少是否抑制酒精促进的肝脏肿瘤形成。 这些目标的成功实现将大大提高我们对分子生物学的理解。 酒精相关性肝癌的机制。用免疫抑制剂抑制Brf 1和Pol III基因表达 MSK 1 KO小鼠和他莫昔芬诱导的条件性Brf 1 KO小鼠应导致肝肿瘤的抑制 阵因此，建议项目的结果可以为处理提供潜在的策略 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.