Tumor-promoting liver injuries and mechanisms

这个项目的目标是破译各种肝脏损伤和疾病是如何 加速和加剧肝细胞癌(HCC)的发展，这是主要原因之一 全球与癌症相关的死亡率。当务之急是阐明肿瘤的致癌机制 具有讽刺意味的是，肝脏损伤是由于肝细胞中的致癌分子丢失而造成的。在最近 实验中，我们发现Shp2/Ptpn11的缺失，以前已知是促癌的， 二乙基亚硝胺(DEN)或Pten缺乏症加重肝细胞癌进展 纳什。一致地，其他几个小组报告说，有针对性地去除癌蛋白，如 肝细胞中的c-Met、IKKB和b-catenin确实加重了DEN或 其他致癌驱动因素。然而，其抗肿瘤作用的潜在机制 这些癌蛋白还不清楚。我们的假设是，致癌分子的丢失 在肝脏微环境中产生多种促肿瘤因子，导致 加剧了肿瘤的发生。值得注意的是，这些小鼠肿瘤模型紧密地概括了许多 关于肝癌患者发病过程的几个方面。因此，我们认为，共同的 机制或致癌性肝病在小鼠模型和人类之间是相同的 患者在肿瘤发生和发展中的作用。在这个项目上，我们将推行全面的 分析分子和细胞事件的驱动肝癌发生的几个 老鼠模型。我们提出了以下三个具体目标：1)搜索和识别 C-Met、IKKB、Shp2或b-catenin缺乏的肝脏中的致癌因素；2)确定 这些突变体的突变谱和肝癌的启动；以及3)表征DEN诱导的和 Shp2和IKKB基因缺陷型肝脏的自发性肿瘤发生。这个项目的成功将会 破译共同和独特的驱动肝脏肿瘤发生的机制，并将促进 设计新的、有效的肝癌治疗策略。

The goal of this project is to decipher how various liver injuries and disorders can accelerate and exacerbate development of hepatocellular carcinoma (HCC), one leading cause of cancer-related mortality worldwide. The immediate focus is on elucidating the tumorigenic liver damages generated ironically by loss of pro-oncogenic molecules in hepatocytes. In recent experiments, we found that deletion of Shp2/Ptpn11, previously known to be pro-oncogenic, aggravated HCC development induced by diethylnitrosamine (DEN) or by Pten deficiency and NASH. Consistently, several other groups reported that targeted removal of oncoproteins, such as c-Met, Ikkb, and b-catenin, from hepatocytes indeed aggravated HCC induced by DEN or other oncogenic drivers. However, the underlying mechanisms for the anti-oncogenic effect of these oncoproteins are unclear. Our hypothesis is that loss of the pro-oncogenic molecules generates a variety of tumor-promoting factors in the liver microenvironment, resulting in exacerbated tumorigenesis. Of note, these mouse tumor models closely recapitulate many aspects of the pathogenic process in liver cancer patients. Therefore, we believe that common mechanisms or oncogenic liver disorders are shared between the mouse models and human patients in tumor initiation and progression. On this project, we will pursue a comprehensive analysis of the molecular and cellular events that drive hepato-carcinogenesis using several mouse models. We propose the following three Specific Aims: 1) to search and identify tumorigenic factors in livers deficient for c-Met, Ikkb, Shp2 or b-catenin; 2) to determine the mutation profiles and HCC initiation in these mutants; and 3) to characterize DEN-induced and spontaneous tumorigenesis in liver deficient for both Shp2 and Ikkb. Success of this project will decipher common and distinctive mechanisms that drive liver tumorigenesis, and will facilitate design of novel and effective therapeutic strategies for liver cancer.