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Journal of Cell Communication and Signaling

, Volume 11, Issue 2, pp 155–166 | Cite as

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

  • Evin İşcan
  • Aysim Güneş
  • Peyda Korhan
  • Yeliz Yılmaz
  • Esra Erdal
  • Neşe AtabeyEmail author
RESEARCH ARTICLE

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.

Keywords

c-Met Heparin Hepatocellular carcinoma Invasion Proliferation 

Abbreviations

ANOVA

Analysis of variance

BCA

Bicinchoninic acid

DSs

Dermatan sulfates

DMEM

Dulbecco’s modified eagle medium

EGR1

Early growth response factor 1

ERK1/2

Extracellular signal-regulated kinases

FBS

Fetal bovine serum

GAG

Glycosaminoglycan

GPC3

Glypican 3

Gab1

Grb2 associated binder 1

Grb2

Growth factor receptor-bound protein 2

HSPGs

Heparan sulfate proteoglycans

HCC

Hepatocellular carcinoma

HGF

Hepatocyte growth factor

MMPs

Matrix metalloproteinases

MAPK

Mitogen-activated protein kinase

NFDM

Nonfat dry milk

PBS

Phosphate buffer saline

PI

Propidium iodide

PI3K

Phosphoinositide-3 kinase

PVDF

Polyvinylidene fluoride

SDS

Sodium dodecyl sulphate

SEM

Standard error of the mean

SRB

Sulforhodamin b

TCA

Trichloroacetic acid

TBST

Tris buffered saline/Tween-20

Notes

Acknowledgments

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).

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare

Supplementary material

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Copyright information

© The International CCN Society 2016

Authors and Affiliations

  1. 1.Izmir International Biomedicine and Genome InstituteDokuz Eylul UniversityIzmirTurkey
  2. 2.Department of Medical Biology, Faculty of MedicineDokuz Eylul UniversityIzmirTurkey

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