Overexpression of membrane-type 2 matrix metalloproteinase induced by hypoxia-inducible factor-1α in pancreatic cancer: Implications for tumor progression and prognosis

Abstract

Membrane-type 2 matrix metalloproteinase (MT2-MMP) has been identified as a powerful modulator of the pericellular environment that promotes tumor invasion and metastasis. In this study, we investigated the association of MT2-MMP and hypoxia-inducible factor-1α (HIF-1α) expression in pancreatic cancer with regard to their clinical prognostic significance. Of the tissue specimens obtained from the 78 patients included in this study, 46 (59%) were found to be positive for MT2-MMP immunostaining and MT2-MMP expression was colocalized with HIF-1α in pancreatic cancer. Using the Spearman's rank analysis, the protein and mRNA expression level of MT2-MMP was found to be significantly correlated with HIF-1α and CD34-microvascular density in pancreatic cancer. Furthermore, the expression of MT2-MMP in response to hypoxia was increased in a time-dependent manner and the promoter luciferase reporter revealed upregulation of MT2-MMP expression induced by HIF-1α in pancreatic cancer cells. Moreover, the Cox regression model indicated that MT2-MMP was an independent prognostic factor in patients with pancreatic cancer. Our results demonstrated that the overexpression of MT2-MMP was induced by HIF-1α in response to hypoxia and was an independent prognostic factor for pancreatic cancer progression.