Molecular and cellular communications in liver tumorigenesis

项目描述（由申请人提供）：该项目的目标是描述驱动肝癌发生的分子和细胞机制，目前的重点是破解分子在肝脏肿瘤发生中的双重作用。肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一，尽管其潜在机制尚不清楚。在最近的实验中，我们发现了一种意想不到的抑制肝癌的作用Shp2，一种酪氨酸磷酸酶，以前被认为是促癌的。在老年小鼠中，Shp2的消融促进肝损伤、炎症和肝细胞肿瘤的自发发展。Shp2缺失使小鼠对化学致癌物质诱导的肝肿瘤发生显著敏感。我们还发现Stat3在HCC发展中的促癌和抑癌作用。与我们对Shp2和Stat3的观察结果一致，其他几个研究小组已经发现了hcc抑制作用在先前确定的促肿瘤基因中。尽管潜在的机制仍有待阐明，但一种常见的表型是在肝细胞中去除促生存分子后HCC的发展增强。值得注意的是，这些小鼠肿瘤模型密切概括了人类hcc致病过程的许多方面，包括慢性肝损伤-炎症-代偿性增殖-肝癌发生。因此，我们认为小鼠模型和人类患者在HCC的发生和发展中具有共同的机制。在本项目中，我们将使用已建立的动物模型来解剖肝癌初期、早期和晚期肝脏中的分子和细胞事件。具体而言，我们提出以下3个目标：1)确定HCC起始和驱动肿瘤进展的细胞间通讯的细胞起源性质；2)确定离体肝癌细胞的致瘤特性和异常信号通路；3)破译Stat3在HCC发展中的双重功能。该项目的成功将阐明HCC发生和发展的一般机制，并将促进肝癌新诊断和治疗策略的设计。

DESCRIPTION (provided by applicant): The goal of this project is to delineate the molecular and cellular mechanisms that drive hepatocarcinogenesis, and the immediate focus is on deciphering dual roles of molecules in liver tumorigenesis. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, although the underlying mechanisms are poorly understood. In most recent experiments, we have found an unanticipated HCC- suppressing effect of Shp2, a tyrosine phosphatase previously known to be pro-oncogenic. Ablation of Shp2 promotes hepatic damage, inflammation, and spontaneous development of hepatocellular tumors in aged mice. Shp2 loss dramatically sensitizes the mice to chemical carcinogen-induced liver tumorigenesis. We have also found pro- and anti-oncogenic actions of Stat3 in HCC development. Consistent with our observations on Shp2 and Stat3, several other groups have identified HCC-inhibitory effects in genes previously identified as pro-tumorigenic. Although the underlying mechanisms remain to be elucidated, one common phenotype is the augmented HCC development following removal of a pro-survival molecule from hepatocytes. Of note, these mouse tumor models closely recapitulate many aspects of the pathogenic process in human HCCs, involving chronic hepatic injury-inflammation-compensatory proliferation-hepatocarcinogenesis. Therefore, we believe that common mechanisms are shared between the mouse models and human patients in HCC initiation and development. On this project, we will use the established animal models to dissect the molecular and cellular events in the liver at initial, early and late stages of hepatocarcinomas. Specifically, we propose the following 3 Aims: 1) to determine the nature of cell origin in HCC initiation and cell-cell communications driving tumor progression; 2) to determine the tumorigenic properties and aberrant signaling pathways of isolated hepatoma cells; and 3) to decipher the dual functions of Stat3 in HCC development. Success of this project will illustrate a general mechanism underlying HCC initiation and progression, and will also facilitate design of novel diagnostic and therapeutic strategies for hepatocarcinoma.