Dissection of Pten-regulated signals in hepatopathogenesis

 描述（由申请人提供）：众所周知，一个基因突变不足以触发肿瘤发生，因此一个紧迫的问题是阐明各种原癌事件如何协同作用以驱动肿瘤发生。原发性肝癌，特别是肝细胞癌（HCC），是癌症相关死亡的第二大原因。缺乏对HCC分子发病机制的了解，阻碍了我们设计基于机制的治疗策略。在许多肝癌患者中检测到Pten肿瘤抑制基因的突变和沉默，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HCC的发展。流行病学分析清楚地表明，在全球80%的确诊病例中，HCC与慢性B或丙型肝炎病毒（HBV或HCV）感染密切相关。然而，大多数肝炎患者不会发展成HCC，这表明在诱导肝癌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Shp 2（一种酪氨酸磷酸酶）的额外缺失显著增强和加速了Pten丢失诱导的HCC发展。Pten和Shp 2双敲除（DKO）小鼠在7个月内以100%的转化率发展HCC。使用这种新的复合突变小鼠系，具有明确的肝肿瘤发生动力学和明确的遗传缺陷，我们将确定Pten缺乏如何与HCC发展中的其他肿瘤促进事件合作。我们还将通过将肝细胞特异性Pten或Shp 2 KO小鼠与HBV转基因小鼠杂交来产生新的小鼠品系，以确定病毒感染与宿主细胞缺陷在驱动肝脏发病机制中的动态相互作用。我们将进行RNA-seq和生物信息学分析，以了解驱动HCC启动的信号通路以及肿瘤发生所需的肿瘤细胞内在信号和肝脏环境信号。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HCC发生和发展机制的最有力方法。

 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.