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Hepatology. 2015 Jul;62(1):166-78. doi: 10.1002/hep.27798. Epub 2015 Apr 22.

Matrix metalloproteinase 10 contributes to hepatocarcinogenesis in a novel crosstalk with the stromal derived factor 1/C-X-C chemokine receptor 4 axis.

Author information

1
Division of Hepatology, CIMA, University of Navarra, Pamplona, Spain.
2
Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
3
Microscopic and Ultrastructural Anatomy, Center for Integrated Biomedical Research- CIR, University Campus Bio-Medico of Rome, Rome, Italy.
4
CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain.
5
Hepatology Unit, University Campus Bio-Medico of Rome, Rome, Italy.
6
Department of Digestive Diseases, Hospital Clinico San Carlos, Madrid, Spain.
7
Division of Cardiovascular Sciences, CIMA, University of Navarra, Pamplona, Spain.

Abstract

Matrix metalloproteinases (MMPs) participate in tissue repair after acute injury, but also participate in cancer by promoting a protumorigenic microenvironment. Previously, we reported on a key role for MMP10 in mouse liver regeneration. Herein, we investigated MMP10 expression and function in human hepatocellular carcinoma (HCC) and diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis. MMP10 was induced in human and murine HCC tissues and cells. MMP10-deficient mice showed less HCC incidence, smaller histological lesions, reduced tumor vascularization, and less lung metastases. Importantly, expression of the protumorigenic, C-X-C chemokine receptor-4 (CXCR4), was reduced in DEN-induced MMP10-deficient mice livers. Human HCC cells stably expressing MMP10 had increased CXCR4 expression and migratory capacity. Pharmacological inhibition of CXCR4 significantly reduced MMP10-stimulated HCC cell migration. Furthermore, MMP10 expression in HCC cells was induced by hypoxia and the CXCR4 ligand, stromal-derived factor-1 (SDF1), through the extracellular signal-regulated kinase 1/2 pathway, involving an activator protein 1 site in MMP10 gene promoter.

CONCLUSION:

MMP10 contributes to HCC development, participating in tumor angiogenesis, growth, and dissemination. We identified a new reciprocal crosstalk between MMP10 and the CXCR4/SDF1 axis contributing to HCC progression and metastasis. To our knowledge, this is the first report addressing the role of a MMP in hepatocarcinogenesis in the corresponding genetic mouse model.

PMID:
25808184
DOI:
10.1002/hep.27798
[Indexed for MEDLINE]

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