Transcriptional upregulation of MT2-MMP in response to hypoxia is promoted by HIF-1α in cancer cells.

Hypoxia is a critical event in solid tumor development, invasion, and metastasis. Cellular adaptation to hypoxic microenvironment is essential for tumor progression and is largely mediated by hypoxia-inducible factor-1α (HIF-1α) through coordinated regulation of hypoxia-responsive genes. In this study, we found that membrane type-2 matrix metalloproteinase (MT2-MMP), one of the matrix metalloproteinase (MMP) family members, was a novel hypoxia-responsive gene and was upregulated by HIF-1α under hypoxia. When cancer cells were subjected to hypoxia (1% O(2) ) treatment, the mRNA and protein levels of MT2-MMP were significantly increased in a time-dependent manner in all three tested cancer cell lines including pancreatic cancer cells (PANC-1), nonsmall cell lung cancer cells (A-549), and cervix cancer cells (HeLa). Further analyses indicated that there were two hypoxia-responsive elements (HREs) in the MT2-MMP promoter, and HRE1 but not HRE2 was essential for MT2-MMP transcriptional activation under hypoxia. HIF-1α specifically and directly bound to MT2-MMP promoter was analyzed by HIF-1α binding/competition and chromatin immunoprecipitation (ChIP) assays. Furthermore, we found that upregulation of MT2-MMP under hypoxia could confer resistance to hypoxia-induced apoptosis and increase invasiveness of cancer cells. These findings provided a new insight into how cancer cells overcome hypoxic stress and trend to survive and invade, demonstrated a new regulatory mechanism of MT2-MMP expression in caner cells, and also revealed that MT2-MMP was a novel hypoxia-responsive gene and was upregulated by HIF-1α under hypoxia. © 2011 Wiley-Liss, Inc.