title: Matrix metalloproteinase 10 contributes to hepatocarcinogenesis in a novel crosstalk with the stromal derived factor 1/C-X-C chemokine receptor 4 axis.
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.
  
  
  CONCLUSIONS
  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.
authors: Division of Hepatology, CIMA, University of Navarra, Pamplona, Spain.
authors: Oihane
authors: O
authors: García-Irigoyen
authors: Division of Hepatology, CIMA, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Maria U
authors: MU
authors: Latasa
authors: Microscopic and Ultrastructural Anatomy, Center for Integrated Biomedical Research- CIR, University Campus Bio-Medico of Rome, Rome, Italy.
authors: Simone
authors: S
authors: Carotti
authors: Division of Hepatology, CIMA, University of Navarra, Pamplona, Spain.|CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Iker
authors: I
authors: Uriarte
authors: Division of Hepatology, CIMA, University of Navarra, Pamplona, Spain.
authors: Maria
authors: M
authors: Elizalde
authors: Division of Hepatology, CIMA, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Raquel
authors: R
authors: Urtasun
authors: Hepatology Unit, University Campus Bio-Medico of Rome, Rome, Italy.
authors: Umberto
authors: U
authors: Vespasiani-Gentilucci
authors: Microscopic and Ultrastructural Anatomy, Center for Integrated Biomedical Research- CIR, University Campus Bio-Medico of Rome, Rome, Italy.
authors: Sergio
authors: S
authors: Morini
authors: Department of Digestive Diseases, Hospital Clinico San Carlos, Madrid, Spain.
authors: Patricia
authors: P
authors: Benito
authors: Department of Digestive Diseases, Hospital Clinico San Carlos, Madrid, Spain.
authors: Jose M
authors: JM
authors: Ladero
authors: Division of Cardiovascular Sciences, CIMA, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Jose A
authors: JA
authors: Rodriguez
authors: Division of Hepatology, CIMA, University of Navarra, Pamplona, Spain.|CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain.
authors: Jesus
authors: J
authors: Prieto
authors: Division of Cardiovascular Sciences, CIMA, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Josune
authors: J
authors: Orbe
authors: Division of Cardiovascular Sciences, CIMA, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Jose A
authors: JA
authors: Páramo
authors: Division of Hepatology, CIMA, University of Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Maite G
authors: MG
authors: Fernández-Barrena
authors: Division of Hepatology, CIMA, University of Navarra, Pamplona, Spain.|CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Carmen
authors: C
authors: Berasain
authors: Division of Hepatology, CIMA, University of Navarra, Pamplona, Spain.|CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Matias A
authors: MA
authors: Avila
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000209:etiology*; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D020239:Receptor Cross-Talk; D019718:Receptors, CXCR4 / Q000378:metabolism*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D053506:Matrix Metalloproteinase 10