Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide and most patients with HCC have limited treatment options. Focal adhesion kinase (FAK) is overexpressed in many HCC specimens, offering a potential target for HCC treatment. However, the role of FAK in hepatocarcinogenesis remains elusive. Establishing whether FAK expression plays a role in HCC development is necessary to determine whether it is a viable therapeutic target. In this study, we generated mice with hepatocyte-specific deletion of Fak and investigated the role of Fak in an oncogenic (c-MET/β-catenin, MET/CAT)-driven HCC model. We found that deletion of Fak in hepatocytes did not affect morphology, proliferation, or apoptosis. However, Fak deficiency significantly repressed MET/CAT-induced tumor development and prolonged survival of animals with MET/CAT-induced HCC. In mouse livers and HCC cell lines, Fak was activated by MET, which induced the activation of Akt/Erk and up-regulated cyclin D1 and tumor cell proliferation. CAT enhanced MET-stimulated FAK activation and synergistically induced the activation of the AKT/ERK-cyclin D1 signaling pathway in a FAK kinase-dependent manner. In addition, FAK was required for CAT-induced cyclin D1 expression in a kinase-independent fashion. Fak is required for c-Met/β-catenin-driven hepatocarcinogenesis. Inhibition of FAK provides a potential strategy to treat HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most common type of liver cancer
There was no significant difference in morphology and histology of livers between HepWT and HepΔFak mice (Fig. 1C, 1D, and S2)
Fak deficiency did not affect cell proliferation or apoptosis in mouse liver (Fig. 1E and 1F). These results suggest that deletion of Fak in hepatocytes does not affect mouse liver homeostasis
Summary
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. HCC is the fifth leading cancer and the third most common cause for cancer death in the world [1]. The major causes of HCC are liver disease due to viral hepatitis, alcohol use, and non-alcoholic steatohepatitis (NASH) [2]. HCC can be treated to achieve long-term survival by surgical resection, liver transplantation and locoregional therapy if patients are diagnosed at an early stage [3]. The current most effective targeted therapeutic agent for advanced HCC, Sorafenib, only increased survival from 7.9 months to 10.7 months [5]. It is urgent to develop newer and more effective therapeutic strategies and agents to treat HCC. To achieve this goal, it is necessary to elucidate the molecular signaling pathways which drive or mediate the development of HCC
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