title: The regulatory role of heparin on c-Met signaling in hepatocellular carcinoma cells.
abstract: The role of heparin as an anticoagulant is well defined; however, its role in tumorigenesis and tumor progression is not clear yet. Some studies have shown that anticoagulant treatment in cancer patients improve overall survival, however, recent clinical trials have not shown a survival benefit in cancer patients receiving heparin treatment. In our previous studies we have shown the inhibitory effects of heparin on Hepatocyte Growth Factor (HGF)-induced invasion and migration in hepatocellular carcinoma (HCC) cells. In this study, we showed the differential effects of heparin on the behaviors of HCC cells based on the presence or absence of HGF. In the absence of HGF, heparin activated HGF/c-Met signaling and promoted motility and invasion in HCC cells. Heparin treatment led to c-Met receptor dimerization and activated c-Met signaling in an HGF independent manner. Heparin-induced c-Met activation increased migration and invasion through ERK1/2, early growth response factor 1 (EGR1) and Matrix Metalloproteinases (MMP) axis. Interestingly, heparin modestly decreased the proliferation of HCC cells by inhibiting activatory phosphorylation of Akt. The inhibition of c-Met signaling reversed heparin-induced increase in motility and invasion and, proliferation inhibition. Our study provides a new perspective into the role of heparin on c-Met signaling in HCC.
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey.
authors.forename: Evin
authors.initials: E
authors.lastname: İşcan
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey.|Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Aysim
authors.initials: A
authors.lastname: Güneş
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Peyda
authors.initials: P
authors.lastname: Korhan
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey.|Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Yeliz
authors.initials: Y
authors.lastname: Yılmaz
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey.|Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Erdal
authors.affiliation: Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey. nese.atabey@deu.edu.tr.|Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey. nese.atabey@deu.edu.tr.
authors.forename: Neşe
authors.identifier: http://orcid.org/0000-0003-4966-2980
authors.initials: N
authors.lastname: Atabey
keywords: Heparin; Hepatocellular carcinoma; Invasion; Proliferation; c-Met