Upregulation of Brf1 (TFIIB-related factor 1) and Pol III gene (RNA polymerase III-dependent gene, such as tRNAs and 5S rRNA) activities is associated with cell transformation and tumor development. Alcohol intake causes liver injury, such as steatosis, inflammation, fibrosis, and cirrhosis, which enhances the risk of HCC development. However, the mechanism of alcohol-promoted HCC remains to be explored. We have designed the complementary research system, which is composed of cell lines, an animal model, human samples, and experiments in vivo and in vitro, to carry out this project by using molecular biological, biochemical, and cellular biological approaches. It is a unique system to explore the mechanism of alcohol-associated HCC. Our results indicate that alcohol upregulates Brf1 and Pol III gene (tRNAs and 5S rRNA) transcription in primary mouse hepatocytes, immortalized mouse hepatocyte-AML-12 cells, and engineered human HepG2-ADH cells. Alcohol activates MSK1 to upregulate expression of Brf1 and Pol III genes, while inhibiting MSK1 reduces transcription of Brf1 and Pol III genes in alcohol-treated cells. The inhibitor of MSK1, SB-747651A, decreases the rates of cell proliferation and colony formation. Alcohol feeding promotes liver tumor development of the mouse. These results, for the first time, show the identification of the alcohol-response promoter fragment of the Pol III gene key transcription factor, Brf1. Our studies demonstrate that Brf1 expression is elevated in HCC tumor tissues of mice and humans. Alcohol increases cellular levels of Brf1, resulting in enhancement of Pol III gene transcription in hepatocytes through MSK1. Our mechanism analysis has demonstrated that alcohol-caused high-response fragment of the Brf1 promoter is at p-382/+109bp. The MSK1 inhibitor SB-747651A is an effective reagent to repress alcohol-induced cell proliferation and colony formation, which is a potential pharmaceutical agent. Developing this inhibitor as a therapeutic approach will benefit alcohol-associated HCC patients.

中文翻译：

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丝裂原和应激激活的蛋白激酶1介导酒精上调的Brf1和tRNA基因转录，导致表型改变。

Brf1（TFIIB相关因子1）和Pol III基因（RNA聚合酶III依赖性基因，例如tRNA和5S rRNA）的上调与细胞转化和肿瘤发展有关。饮酒会导致肝损伤，例如脂肪变性，炎症，纤维化和肝硬化，从而增加发生HCC的风险。然而，酒精促进肝癌的机制仍有待探索。我们设计了互补的研究系统，该系统由细胞系，动物模型，人类样品以及体内和体外实验组成，以利用分子生物学，生化和细胞生物学方法来执行此项目。这是探索与酒精相关的HCC机理的独特系统。我们的结果表明，酒精会上调小鼠原代肝细胞，永生化小鼠肝细胞AML-12细胞和工程人类HepG2-ADH细胞中的Brf1和Pol III基因（tRNA和5S rRNA）转录。酒精激活MSK1以上调Brf1和Pol III基因的表达，而抑制MSK1则降低酒精处理细胞中Brf1和Pol III基因的转录。MSK1的抑制剂SB-747651A可降低细胞增殖和集落形成的速率。饮酒可促进小鼠肝肿瘤的发展。这些结果是第一次 展示了Pol III基因关键转录因子Brf1的酒精反应启动子片段的鉴定。我们的研究表明，Brf1表达在小鼠和人类的HCC肿瘤组织中升高。酒精会增加Brf1的细胞水平，从而通过MSK1增强肝细胞中Pol III基因的转录。我们的机理分析表明，酒精引起的Brf1启动子高响应片段位于p-382 / + 109bp。MSK1抑制剂SB-747651A是抑制酒精诱导的细胞增殖和集落形成的有效试剂，它是一种潜在的药物。开发这种抑制剂作为治疗方法将使酒精相关的HCC患者受益。酒精会增加Brf1的细胞水平，从而通过MSK1增强肝细胞中Pol III基因的转录。我们的机理分析表明，酒精引起的Brf1启动子高响应片段位于p-382 / + 109bp。MSK1抑制剂SB-747651A是抑制酒精诱导的细胞增殖和集落形成的有效试剂，它是一种潜在的药物。开发这种抑制剂作为治疗方法将使酒精相关的HCC患者受益。酒精会增加Brf1的细胞水平，从而通过MSK1增强肝细胞中Pol III基因的转录。我们的机理分析表明，酒精引起的Brf1启动子高响应片段位于p-382 / + 109bp。MSK1抑制剂SB-747651A是抑制酒精诱导的细胞增殖和集落形成的有效试剂，它是一种潜在的药物。开发这种抑制剂作为治疗方法将使酒精相关的HCC患者受益。MSK1抑制剂SB-747651A是抑制酒精诱导的细胞增殖和集落形成的有效试剂，它是一种潜在的药物。开发这种抑制剂作为治疗方法将使酒精相关的HCC患者受益。MSK1抑制剂SB-747651A是抑制酒精诱导的细胞增殖和集落形成的有效试剂，它是一种潜在的药物。开发这种抑制剂作为治疗方法将使酒精相关的HCC患者受益。