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.