Resumen de Función de la metaloproteasa de matriz 10 (MMP10) en la regeneración hepática y la carcinogénesis
Upon tissue injury, the liver mounts a potent reparative and regenerative response. This wound-healing response involves a transitory substitution of damaged hepatic parenchyma by extracellular matrix (ECM) that subsequently needs to be removed when liver tissue is regenerated. A role for proteases, including matrix metalloproteinases (MMPs), in this process is increasingly recognized, acting as regulatory molecules by the selective proteolytic activation of growth factors and cell surface receptors in addition to their ability to degrade ECM constituents. Moreover, MMPs also have been demonstrated to participate in cancer by promoting a protumorigenic microenvironment. We have evaluated the hepatic expression and function of MMP10 (stromelysin-2) in mouse models of liver wound-healing and regeneration, in human hepatocellular carcinoma (HCC) and in diethylnitrosamine (DEN)-induced mouse hepatocarcinogenesis. The role of MMP10 was evaluated by comparing the response of wild type (MMP10+/+) and MMP10-deficient (MMP10-/-) mice to the different experimental models. Mouse MMP10 hepatic expression was readily induced in different injury and regeneration models: two-thirds partial hepatectomy (PH), bile duct ligation (BDL) and carbon tetrachloride (CCl4) acute administration. MMP10 protein was detected in hepatocytes, cholangiocytes and macrophages. MMP10 was also induced in human and murine HCC tissues and cells. In cultured liver epithelial cells, MMP10 expression was additively induced by transforming growth factor-ß and epidermal growth factor receptor ligands. TLR4 ligands also stimulated its expression in macrophages. Lack of MMP10 resulted in increased liver injury and fibrogenesis, impaired resolution of necrotic areas and defective turnover of fibrin(ogen) and fibronectin upon PH, BDL and CCl4 administration. On the other hand, in the DEN model, MMP10-/- 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 those mice. A MMP10 overexpressing human HCC cell line was generated. These HCC cells had increased CXCR4 expression and showed enhanced migratory capacity, and the pharmacological inhibition of CXCR4 reduced MMP10-stimulated cell migration. MMP10 expression in HCC cells was induced by hypoxia and the CXCR4 ligand stroma-derived factor 1 (SDF1), through the ERK1/2 pathway, involving an activator protein 1 site in MMP10 gene promoter. Conclusions: MMP10 expression is induced during mouse liver injury and participates in the hepatic wound-healing response, where the profibrinolytic activity of MMP10 may be essential in this hepatoprotective role. In contrast, 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.
