Dissection of Pten-regulated signals in hepatopathogenesis

 描述(申请人提供)：众所周知，一个基因突变不足以触发肿瘤的发生，因此，一个紧迫的问题是阐明各种致癌事件如何协同作用于肿瘤的启动。原发性肝癌，特别是肝细胞癌，是癌症相关死亡的第二大原因。由于缺乏对肝细胞癌分子发病机制的了解，我们无法设计基于机制的治疗策略。在许多肝癌患者中已经检测到Pten抑癌基因的突变和沉默，但目前尚不清楚Pten缺陷如何与其他细胞信号转导障碍相互作用促进肝癌的发展。流行病学分析清楚地表明，在全世界80%的确诊病例中，肝细胞癌与慢性乙肝或丙型肝炎病毒(乙肝或丙型肝炎病毒)感染有很强的相关性。然而，大多数肝炎患者不会发生肝细胞癌，这表明在诱导肝肿瘤的发生中需要宿主细胞缺陷。在最近的实验中，我们发现肝细胞中Shp2(一种酪氨酸磷酸酶)的额外缺失显著地增强和加速了由Pten丢失引起的肝细胞癌的发展。Pten和Shp2双基因敲除(DKO)小鼠在7个月内形成100%外显率的肝癌。利用这一新的具有明确的肝脏肿瘤发生动力学和明确的遗传缺陷的新的复合突变小鼠系，我们将确定Pten缺陷如何与其他促肿瘤事件在肝细胞癌的发展中协同作用。我们还将通过将肝细胞特异性的Pten或Shp2 KO小鼠与乙肝转基因小鼠杂交来产生新的小鼠系，以确定病毒感染与宿主细胞缺陷在推动肝脏疾病发生中的动态相互作用。我们将进行RNA-SEQ和生物信息学分析，以了解驱动肝细胞癌启动的信号通路，以及肿瘤细胞内在的和肿瘤发生所需的肝脏环境信号。我们相信，使用多学科工具对动物肿瘤模型进行深入的分子和细胞分析，将是破译肝细胞癌发生和发展机制的最有力的途径。

 DESCRIPTION (provided by applicant): It is well known that one gene mutation is not sufficient to trigger tumorigenesis, and therefore one urgent issue is to elucidate how various pro-oncogenic events work cooperatively in driving tumor initiation. Primary liver cancers, in particular hepatocellular carcinoma (HCC), are the 2nd leading cause of cancer-related deaths. Lack of understanding of the molecular pathogenesis for HCC has prevented us from designing mechanism-based therapeutic strategies. Mutations and silencing of Pten tumor suppressor have been detected in many liver cancer patients, but it is unclear how Pten deficiency interacts with other cell signaling disorders in promoting HCC development. Epidemiological analyses clearly indicate a strong association of HCC with chronic hepatitis B or C virus (HBV or HCV) infection in 80% of the diagnosed cases worldwide. However, the majority of hepatitis patients do NOT develop HCCs, indicating requirement of host cell defects in inducing hepato-oncogenesis. In most recent experiments, we found that additional deletion of Shp2 (a tyrosine phosphatase) in hepatocytes dramatically enhanced and accelerated HCC development induced by Pten loss. The Pten and Shp2 double knockout (DKO) mice developed HCCs at 100% penetrance in 7 months. Using this new compound mutant mouse line with defined kinetics of liver tumorigenesis and clear genetic defects, we will determine how Pten deficiency cooperates with additional tumor-promoting events in HCC development. We will also generate new mouse lines by crossing hepatocyte-specific Pten or Shp2 KO mouse with HBV transgenic mouse, to determine the dynamic interplay of viral infection with host cell defects in driving hepatopathogenesis. We will perform RNA-seq and bioinformatics analyses, to understand signaling pathways driving HCC initiation and also tumor cell-intrinsic as well as hepatic environmental signals required for tumorigenesis. We believe that in-depth molecular and cellular analyses of animal tumor models, using multidisciplinary tools, will be a most powerful approach to decipher the mechanisms underlying HCC initiation and progression.