title: FAK is required for c-Met/β-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/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.
  
  
  CONCLUSIONS
  Fak is required for c-Met/β-catenin-driven hepatocarcinogenesis. Inhibition of FAK provides a potential strategy to treat HCC.
authors.affiliation: Department of Surgery and Oncology Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL.
authors.forename: Na
authors.initials: N
authors.lastname: Shang
authors.forename: Maribel
authors.initials: M
authors.lastname: Arteaga
authors.forename: Ali
authors.initials: A
authors.lastname: Zaidi
authors.forename: Jimmy
authors.initials: J
authors.lastname: Stauffer
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Cotler
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Zeleznik-Le
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; C530105:Ccnd1 protein, mouse; D051176:beta Catenin; D019938:Cyclin D1; D019859:Proto-Oncogene Proteins c-met; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496051:Ptk2 protein, mouse; C496053:Ptk2b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases