The regulatory role of heparin on c-Met signaling in hepatocellular carcinoma cells


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.

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Analysis of variance


Bicinchoninic acid


Dermatan sulfates


Dulbecco’s modified eagle medium


Early growth response factor 1


Extracellular signal-regulated kinases


Fetal bovine serum




Glypican 3


Grb2 associated binder 1


Growth factor receptor-bound protein 2


Heparan sulfate proteoglycans


Hepatocellular carcinoma


Hepatocyte growth factor


Matrix metalloproteinases


Mitogen-activated protein kinase


Nonfat dry milk


Phosphate buffer saline


Propidium iodide


Phosphoinositide-3 kinase


Polyvinylidene fluoride


Sodium dodecyl sulphate


Standard error of the mean


Sulforhodamin b


Trichloroacetic acid


Tris buffered saline/Tween-20


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We thank Prof. Brian Carr for critically reading the manuscript and improving the English. This work was supported by The Scientific and Technological Research Council of Turkey (Project # 110S349).

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Correspondence to Neşe Atabey.

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Evin Iscan and Aysim Gunes contributed equally to this work.

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İşcan, E., Güneş, A., Korhan, P. et al. The regulatory role of heparin on c-Met signaling in hepatocellular carcinoma cells. J. Cell Commun. Signal. 11, 155–166 (2017).

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  • c-Met
  • Heparin
  • Hepatocellular carcinoma
  • Invasion
  • Proliferation