The role of FAK in hepatocarcinogenesis

描述（由申请人提供）：本申请的中心焦点是了解粘着斑激酶（FAK）在肝癌中的作用。肝细胞癌（HCC）是美国增长最快的癌症。目前，HCC的潜在机制尚不完全清楚。了解驱动或介导HCC发展的分子信号通路对于确定预防或治疗HCC的新治疗靶点非常重要。FAK已被证明在多种组织的肿瘤发生和癌症进展中起重要作用，然而，由于缺乏体内研究，FAK在肝癌中的作用仍然难以捉摸。目前，几种FAK抑制剂正被用作早期临床试验中有前途的抗实体瘤药物。由于大多数药物代谢发生在肝脏，因此了解FAK抑制对肝脏的影响至关重要。我们发现FAK的缺失 在肝细胞特异性磷酸酶和张力蛋白同源物（PTEN）缺陷小鼠中促进脂肪性肝炎、肝纤维化和肝增殖。由于脂肪性肝炎、肝纤维化和增强的肝增殖被认为促进肝癌，我们提出在肝细胞特异性PTEN缺陷小鼠模型中，肝中FAK的缺失促进肝癌发生。然后，我们打算了解FAK在肝癌发生中的作用，其中FAK的激活不是由于PTEN的丢失。为了实现这一目标，我们计划使用致癌物二乙基亚硝胺（DEN）诱导的HCC小鼠模型，其中FAK的激活不是由于PTEN的丢失。这项研究将为FAK在肝癌中的作用提供新的见解，这对于通过靶向FAK治疗肝癌或其他类型的癌症非常重要。

DESCRIPTION (provided by applicant): The central focus of this application is to understand the role of focal adhesion kinase (FAK) in liver cancer. Hepatocellular carcinoma (HCC) is the most rapidly increasing cancer in the United States. Currently, the underlying mechanisms of HCC are not fully known. Understanding the molecular signaling pathways that drive or mediate the development of HCC is important for identifying novel therapeutic targets for preventing or treating HCC. FAK has been shown to play an important role in tumorigenesis and cancer progression in several tissues, however, the role of FAK in liver cancer remains elusive due to the lack of in vivo studies. Currently, several FAK inhibitors are being used as promising anti-solid tumor agents in early-phase clinical trials. As most drug metabolism occurs in the liver, it s critical to understand the effect of inhibition of FAK on liver. We have found that deletion of FAK promotes steatohepatitis, hepatic fibrosis and hepatic proliferation in hepatocyte-specific Phosphatase and Tensin Homolog (PTEN)-deficient mice. As steatohepatitis, hepatic fibrosis and enhanced hepatic proliferation are thought to promote liver cancer, we propose that deletion of FAK in liver promotes hepatocarcinogenesis in hepatocyte- specific PTEN-deficient mice model. We then intend to understand the role of FAK in hepatocarcinogenesis in which activation of FAK is not due to loss of PTEN. To achieve this goal, we plan to use a carcinogen, diethylnitrosamine(DEN)-induced HCC mouse model in which activation of FAK is not due to loss of PTEN. This study will provide new insights into the role of FAK in liver cancer, which is important for treating either liver cancer or other types of cancers by targeting FAK.