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

  • RESEARCH ARTICLE
  • Published:
Journal of Cell Communication and Signaling Aims and scope

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.

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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

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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).

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Authors and Affiliations

  1. Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Balçova, Izmir, Turkey

    Evin İşcan, Aysim Güneş, Yeliz Yılmaz, Esra Erdal & Neşe Atabey

  2. Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey

    Aysim Güneş, Peyda Korhan, Yeliz Yılmaz, Esra Erdal & Neşe Atabey

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  1. Evin İşcan
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  2. Aysim Güneş
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  3. Peyda Korhan
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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). https://doi.org/10.1007/s12079-016-0368-0

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  • DOI: https://doi.org/10.1007/s12079-016-0368-0

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