title: Factor VII promotes hepatocellular carcinoma progression through ERK-TSC signaling.
abstract: We previously demonstrated PAR2 starts upstreamed with tissue factor (TF) and factor VII (FVII), inhibited autophagy via mTOR signaling in HCC. However, the mechanism underlying for merging functions of PAR2 with the coagulation system in HCC progression remained unclear. The present study aimed to investigate the role of TF, FVII and PAR2 in tumor progression of HCC. The expressions of TF, FVII and PAR2 from HCC specimens were evaluated by immunohistochemical stains and western blotting. We found that the expression of FVII, but not TF and PAR2, directly related to the vascular invasion and the clinical staging. Importantly, a lower level of FVII expression was significantly associated with the longer disease-free survival. The addition of FVII but not TF induced the expression of PAR2 and phosphorylation of ERK1/2, whereas knockdown of FVII decreased PAR2 expression and ERK1/2 phosphorylation in HCC cell lines. Furthermore, levels of phosphor-TSC2 (Ser664) were increased after treatment with FVII and PAR2 agonist whereas these were significantly abolished in the presence of a potent and specific MEK/ERK inhibitor U0126. Moreover, mTOR knockdown highly reduced Hep3B migration, which could be reverted by FVII but not TF and PAR2. These results indicated that FVII/PAR2 signaling through MEK/ERK and TSC2 axis for mTOR activation has potent effects on the migration of HCC cells. In addition, FVII/PAR2 signaling elicits an mTOR-independent signaling, which promotes hepatoma cell migration in consistent with the clinical observations. Our study indicates that levels of FVII, but not TF, are associated with tumor migration and invasiveness in HCC, and provides clues that evaluation of FVII expression in HCC may be useful as a prognostic indicator in patients with HCC and may form an alternative target for further therapy.
authors.affiliation: Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: M-C
authors.initials: MC
authors.lastname: Tsai
authors.affiliation: Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan.
authors.forename: K-D
authors.initials: KD
authors.lastname: Chen
authors.affiliation: Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan.
authors.forename: K-T
authors.initials: KT
authors.lastname: Huang
authors.affiliation: Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan.
authors.forename: I-Y
authors.initials: IY
authors.lastname: Kuo
authors.affiliation: Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan.
authors.forename: L-Y
authors.initials: LY
authors.lastname: Chen
authors.affiliation: Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan.
authors.forename: T-H
authors.initials: TH
authors.lastname: Hu
authors.affiliation: Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Fukuoka Institution of Occupational Health, Fukuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Goto
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine , Kaohsiung, Taiwan.
authors.forename: T
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, Guy's Hospital, King's College London, MRC Centre for Transplantation , London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dorling
authors.affiliation: Department of Biochemical Sciences, Faculty of Health and Medical Sciences, University of Surrey , Guildford, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: McVey
authors.affiliation: Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan.
authors.forename: C-L
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Lin