Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Mol Carcinog. 2011 Oct;50(10):770-80. doi: 10.1002/mc.20678. Epub 2011 Jul 12.
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.
缺氧是实体肿瘤发展、侵袭和转移的关键事件。细胞对低氧微环境的适应对于肿瘤的进展至关重要，主要是通过缺氧诱导因子-1α（HIF-1α）通过协调调节缺氧反应基因来介导的。在这项研究中，我们发现膜型 2 基质金属蛋白酶（MT2-MMP）是基质金属蛋白酶（MMP）家族成员之一，是一种新的缺氧反应基因，在缺氧下由 HIF-1α上调。当癌细胞受到缺氧（1%O(2)）处理时，在三种测试的癌细胞系（包括胰腺癌细胞（PANC-1）、非小细胞肺癌细胞（A-549）和宫颈癌细胞（HeLa））中，MT2-MMP 的 mRNA 和蛋白水平均随时间呈时间依赖性显著增加。进一步分析表明，MT2-MMP 启动子中有两个缺氧反应元件（HREs），而 HRE1 而不是 HRE2 是缺氧下 MT2-MMP 转录激活所必需的。通过 HIF-1α 结合/竞争和染色质免疫沉淀（ChIP）实验分析了 HIF-1α 特异性和直接结合到 MT2-MMP 启动子上的情况。此外，我们发现缺氧下 MT2-MMP 的上调可以赋予癌细胞对缺氧诱导的凋亡的抗性，并增加癌细胞的侵袭性。这些发现为癌细胞如何克服低氧应激并倾向于存活和侵袭提供了新的见解，展示了癌细胞中 MT2-MMP 表达的新调节机制，也揭示了 MT2-MMP 是一种新的缺氧反应基因，并在缺氧下由 HIF-1α 上调。
