HEPATIC CARCINOGENESIS: MOLECULAR MECHANISMS

描述(申请人提供)：肝细胞癌是世界上最常见的肿瘤之一。分化的肝细胞处于静止状态，但在肝细胞损伤、肝部分切除和生长介质(如转化生长因子α)的作用下仍具有增殖能力。尽管转化生长因子α是肝细胞增殖和肝肿瘤发生的有效诱导剂，但这种细胞因子的作用机制还不完全清楚。大鼠、鸡或人C/EBPβ通过磷酸化而增加转录活性是由细胞增殖刺激剂诱导的。我们已经报道，从C/EBPbeta-/-而不是从C/EBPbeta+/+分离的原代肝细胞不能对TGFpha产生反应而增殖。这项应用的长期目标是了解肝细胞癌发生的分子机制。 其具体目的是分析C/EBPbeta(Thr217)位点特异性磷酸化在肝细胞癌发生发展中的作用。人肝细胞癌中是否存在磷酸化C/EBPbeta将用针对该表位的特异性抗体来确定。同样，C/EBP的功能增益突变？磷酸化位点(在人类中保守)可能与慢性肝病患者肝肿瘤的发病有关。此外，该协会将接受最先进的遗传学、肝细胞癌的病理生理学和临床方面的强化培训，以及研究报告和补助金和手稿的审查。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma is one of the most prevalent tumors worldwide. Differentiated hepatocytes are quiescent yet have the ability to proliferate in response to hepatocellular injury, partial hepatectomy and growth mediators, such as transforming growth factor alpha (TGFalpha). Although TGFalpha is a potent inducer of hepatocyte proliferation and liver tumorigenesis, the molecular mechanisms responsible for the effects of this cytokine are only partially understood. Increased transcriptional activity through phosphorylations of rat, chicken or human C/EBPbeta is induced by stimulators of cell proliferation. We have reported that primary hepatocytes isolated from C/EBPbeta-/-, but not from C/EBPbeta+/+, mice fail to proliferate in response to TGFalpha. The long-term objectives of this application are to understand the molecular mechanisms responsible for the development of hepatocellular carcinoma. The specific aim is to analyze the role of a site-specific phosphorylation of C/EBPbeta (Thr217) on the development of hepatocellular carcinoma. The presence of phosphorylated C/EBPbeta in human hepatocellular carcinoma will be determined with specific antibodies against this epitope. Similarly, gain-of-function mutations of the C/EBP? phosphorylation site (conserved in humans) could contribute to the pathogenesis of liver tumors in patients with chronic liver diseases. In addition, the PI will receive intensive training in the state-of-the-art genetics, pathophysiological and clinical aspects of hepatocellular carcinoma, as well as research presentations and the reviewing of grants and manuscripts.