HEPATIC CARCINOGENESIS: MOLECULAR MECHANISMS

描述（由申请人提供）：肝细胞癌是全球最常见的肿瘤之一。 分化的肝细胞是静止的，但具有响应于肝细胞损伤、部分肝切除术和生长介质如转化生长因子α（TGF α）而增殖的能力。 虽然TGF α是肝细胞增殖和肝肿瘤发生的有效诱导剂，但对这种细胞因子作用的分子机制仅部分了解。 通过大鼠、鸡或人C/EBP β的磷酸化增加的转录活性由细胞增殖刺激物诱导。 我们已经报道了从C/EBP β-/-小鼠中分离的原代肝细胞，而不是从C/EBP β +/+小鼠中分离的原代肝细胞，不能对TGF α产生应答而增殖。 本申请的长期目标是了解负责肝细胞癌发展的分子机制。 具体目的是分析C/EBP β（Thr 217）的位点特异性磷酸化对肝细胞癌发展的作用。 人肝细胞癌中磷酸化C/EBP β的存在将用针对该表位的特异性抗体测定。 同样，获得的功能突变的C/EBP？磷酸化位点（在人类中保守）可能有助于慢性肝病患者肝肿瘤的发病机制。 此外，PI将接受肝细胞癌最先进的遗传学，病理生理学和临床方面的强化培训，以及研究报告和赠款和手稿的审查。

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.