title: Transcriptional upregulation of MT2-MMP in response to hypoxia is promoted by HIF-1α in cancer cells.
abstract: 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.
authors.affiliation: Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shikai
authors.initials: S
authors.lastname: Zhu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
authors.forename: Hanqing
authors.initials: H
authors.lastname: Wu
authors.forename: Jiongxin
authors.initials: J
authors.lastname: Xiong
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Chunyou
authors.initials: C
authors.lastname: Wang
authors.forename: Heshui
authors.initials: H
authors.lastname: Wu
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D053517:Matrix Metalloproteinase 15 / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015345:Oligonucleotide Probes / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015345:Oligonucleotide Probes; D053517:Matrix Metalloproteinase 15