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

authors

  • GARCÍA IRIGOYEN, OIHANE
  • LATASA, MARÍA U.
  • CAROTTI, SIMONE
  • URIARTE, IKER
  • ELIZALDE, MARÍA
  • URTASUN, RAQUEL
  • VESPASIANI GENTILUCCI, UMBERTO
  • MORINI, SERGIO
  • BENITO, PATRICIA
  • LADERO, JOSÉ M.
  • RODRÍGUEZ, JOSÉ A.
  • PRIETO, JESUS
  • ORBE, JOSUNE
  • PÁRAMO, JOSÉ A.
  • FERNÁNDEZ BARRENA, MAITE G.
  • BERASAIN, CARMEN
  • ÁVILA, MATÍAS A.

publication date

  • July 2015

start page

  • 166

end page

  • 178

issue

  • 1

volume

  • 62

International Standard Serial Number (ISSN)

  • 0270-9139

Electronic International Standard Serial Number (EISSN)

  • 1527-3350

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. (Hepatology 2015;62:166-178)