Brf1在酒精诱导肝细胞癌发生中的作用及分子机制

Hepatocellular Carcinoma (HCC) is one of the main important causes of cancer related death. Incidence of HCC is increasingly worldwide. Studies indicate that alcohol abuse accounts for approximately half of all liver cancer cases. China is a great alcohol consumption country. However, we do not yet have an in-depth study on the molecular mechanism of alcohol-associated HCC. Deregulation of RNA polymerase III-dependent genes (Pol III genes) is tightly linked to cell transformation and tumor development. Brf1 (TFIIB-related factor 1) is a specific transcription factor, which regulates the activities of the class of genes. Our studies have demonstrated that alcohol-feeding HCV-NS5A mice promotes liver tumor development, while Brf1 and Pol III gene transcription are increased in the liver tumor tissues of the mice. Our studies of human HCC samples reveal that Brf1 is overexpressed in most of human HCC cases. High expression of Brf1 is significantly correlated with shorter survival times. These studies imply that Brf1 may play critically important roles in HCC. To explore the molecular mechanism of HCC and identify the direct role of Brf1 in HCC, we have established Brf1 conditional KO mouse. We will analyze the alterations of alcohol-induced deregulation of Brf1 and Pol III genes and investigate the relationship of Brf1 with liver pathology, pathophysiology, alcoholic hepatitis and cirrhosis, and the molecular mechanism of HCC development. Many approaches of cell biology, biochemistry and molecular biology will be utilized to analyze the regulation of Brf1 by alcohol-induced phosphorylation of histone H3. These outcomes will provide scientific basis for alcohol-associated HCC prevention and therapy.

饮酒相关的HCC约占所有肝癌病例的一半，我国尚缺乏这方面的深入研究。RNA Pol III基因的失调与细胞转化和肿瘤发生密切相关。Brf1是一个Pol III 基因特异的转录因子控制这类基因的转录。我们发现在酒精喂养转基因的HCV-NS5A小鼠肝癌发生中，Pol III 基因和Brf1 表达明显增加；HCC病例分析显示Brf1过表达，Brf1高表达的病例生存期明显降低。这表明Brf1 可能在肝癌的发生发展过程中起关键作用。为了探讨Brf1在酒精诱导HCC的作用机制，我们拟采用已建立的肝脏特异诱导的Brf1条件敲除鼠动物模型、RT-PCR等方法分析酒精诱导Brf1 和Pol III 基因失调对HCC发生的影响；应用点突变和质粒转染等方法分析酒精诱导组蛋白H3磷酸化对Brf1的调节。 这些深入系统的研究将揭示Brf1在酒精诱导HCC的作用及其机制，为日后酒精性肝癌的治疗和预防提供科学依。

摄入酒精会导致肝脏损伤，如脂肪变性、炎症、纤维化和肝硬化，从而提高了肝细胞癌（HCC）的发病风险。然而，酒精促发HCC的机制仍有待探索。我们设计了由细胞系、动物模型、临床标本、体内和体外实验组成的互补性研究系统，采取细胞生物学、分子生物学及生物化学等方法来开展这一研究。本研究中，本课题组发现Brf1在酒精诱导的肝细胞癌发生中的促进作用；证实了酒精促进Brf1表达上调和 Pol III基因转录增加；酒精通过激活JNK信号促进Brf1和Pol III基因的表达；酒精通过MSK1增强Brf1基因启动子的活性进而上调Brf1的表达，促进肿瘤细胞的增殖。本研究为酒精性肝癌的治疗和预防提供科学依据。