FAK is required for c-Met/beta-catenin-driven hepatocarcinogenesis Journal Article


Authors: Shang, N; Arteaga, M; Zaidi, A.; Stauffer, J.; Cotler, S. J.; Zeleznik-Le, N. J.; Zhang, J; Qiu, W
Article Title: FAK is required for c-Met/beta-catenin-driven hepatocarcinogenesis
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/beta-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. CONCLUSION: Fak is required for c-Met/beta-catenin-driven hepatocarcinogenesis. Inhibition of FAK provides a potential strategy to treat HCC.
Journal Title: Hepatology (Baltimore, Md.)
Volume: 61
Issue: 1
ISSN: 1527-3350; 0270-9139
Publisher: by the American Association for the Study of Liver Diseases  
Journal Place: United States
Date Published: 2015
Start Page: 214
End Page: 226
Language: eng
DOI/URL:
Notes: LR: 20141231; CI: (c) 2014; GR: R01 HL095896/HL/NHLBI NIH HHS/United States; GR: R01HL095896/HL/NHLBI NIH HHS/United States; GR: R03 CA184652/CA/NCI NIH HHS/United States; GR: R03CA184652/CA/NCI NIH HHS/United States; JID: 8302946; 0 (CTNNB1 protein, mouse); 0 (Ccnd1 protein, mouse); 0 (beta Catenin); 136601-57-5 (Cyclin D1); EC 2.7.10.1 (Proto-Oncogene Proteins c-met); EC 2.7.10.2 (Focal Adhesion Kinase 1); EC 2.7.10.2 (Focal Adhesion Kinase 2); EC 2.7.10.2 (Ptk2 protein, mouse); EC 2.7.10.2 (Ptk2b protein, mouse); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); NIHMS625479; OID: NLM: NIHMS625479 [Available on 01/01/16]; OID: NLM: PMC4280291 [Available on 01/01/16]; PMCR: 2016/01/01 00:00; 2014/04/20 [received]; 2014/08/23 [accepted]; 2014/11/25 [aheadofprint]; ppublish