Molecular and cellular communications in liver tumorigenesis

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，当前的重点是破译分子在肝脏肿瘤发生中的双重作用。肝细胞癌（HCC）是世界范围内癌症相关死亡率的主要原因之一，尽管其潜在机制知之甚少。在最近的实验中，我们发现了Shp 2的一种意想不到的HCC抑制作用，Shp 2是一种酪氨酸磷酸酶，以前已知是促癌的。在老年小鼠中，Shp 2的消融促进肝损伤、炎症和肝细胞肿瘤的自发发展。Shp 2缺失显著地使小鼠对化学致癌物诱导的肝肿瘤发生敏感。我们还发现了Stat 3在HCC发展中的促癌和抑癌作用。与我们对Shp 2和Stat 3的观察一致，其他几个研究小组已经在先前被鉴定为促肿瘤发生的基因中鉴定了HCC抑制作用。虽然潜在的机制仍有待阐明，一个常见的表型是增强HCC的发展后，从肝细胞中去除促生存分子。值得注意的是，这些小鼠肿瘤模型紧密地概括了人类HCC中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，在HCC的发生和发展中，小鼠模型和人类患者之间有共同的机制。在这个项目中，我们将使用已建立的动物模型来解剖肝癌的初始，早期和晚期阶段的肝脏中的分子和细胞事件。具体而言，我们提出了以下3个目标：1）确定HCC起始和细胞间通讯驱动肿瘤进展的细胞起源的性质; 2）确定分离的肝癌细胞的致瘤特性和异常信号通路; 3）破译Stat 3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，也将促进肝癌新的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.