Regulation of Membrane-Type 4 Matrix Metalloproteinase by SLUG Contributes to Hypoxia-Mediated Metastasis
Regulation of Membrane-Type 4 Matrix Metalloproteinase by SLUG Contributes to Hypoxia-Mediated Metastasis
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DOI：
10.1593/neo.91326
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发表时间：
2009-12-01
期刊：
影响因子：
4.8
通讯作者：
Yang, Muh-Hwa
中科院分区：
文献类型：
--
作者：
Huang, Chi-Hung;Yang, Wen-Hao;Yang, Muh-Hwa
低氧肿瘤环境已被证明通过促进血管生成、诱导上皮间质转化（EMT）和获得侵袭潜力对癌症转移至关重要。然而，缺氧对参与侵袭性的蛋白水解酶表达谱的影响相对未知。膜 4 型基质金属蛋白酶 (MT4-MMP) 是一种糖基磷脂酰肌醇锚定蛋白酶，已被证明在人类癌症中过度表达。然而，关于肿瘤细胞中 MT4-MMP 表达的调节和功能的详细机制仍不清楚。在这里，我们证明缺氧或缺氧诱导因子 1 α (HIF-1 α) 的过度表达可诱导人类癌细胞中 MT4-MMP 的表达。 HIF-1 α 激活 SLUG（一种调节人类癌症 EMT 过程的转录因子）对于缺氧条件下诱导 MT4-MMP 至关重要。 SLUG 通过直接结合位于其近端启动子的 E-box 来调节 MT4-MMP 的转录。短干扰RNA介导的MT4-MMP敲低可减弱肿瘤细胞的体外侵袭性和体内肺部定植，而不影响细胞迁移能力。 MT4-MMP 通过调节 MMP 和血管生成因子的表达谱来促进侵袭性和肺部定植。最后，HIF-1 α 和 MT4-MMP 在人类头颈癌中的共表达预示着更差的临床结果。这些发现为缺氧介导的转移建立了一条新的信号通路，并阐明了 MT4-MMP 在癌症转移中的潜在调节机制和功能意义。
The hypoxic tumor environment has been shown to be critical to cancer metastasis through the promotion of angiogenesis, induction of epithelial-mesenchymal transition (EMT), and acquisition of invasive potential. However, the impact of hypoxia on the expression profile of the proteolytic enzymes involved in invasiveness is relatively unknown. Membrane-type 4 matrix metalloproteinase (MT4-MMP) is a glycosyl-phosphatidyl inositol-anchored protease that has been shown to be over-expressed in human cancers. However, detailed mechanisms regarding the regulation and function of MT4-MMP expression in tumor cells remain unknown. Here, we demonstrate that hypoxia or overexpression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) induced MT4-MMP expression in human cancer cells. Activation of SLUG, a transcriptional factor regulating the EMT process of human cancers, by HIF-1 alpha was critical for the induction of MT4-MMP under hypoxia. SLUG regulated the transcription of MT4-MMP through direct binding to the E-box located in its proximal promoter. Short-interference RNA-mediated knockdown of MT4-MMP attenuated in vitro invasiveness and in vivo pulmonary colonization of tumor cells without affecting cell migratory ability. MT4-MMP promoted invasiveness and pulmonary colonization through modulation of the expression profile of MMPs and angiogenic factors. Finally, coexpression of HIF-1 alpha and MT4-MMP in human head and neck cancer was predictive of a worse clinical outcome. These findings establish a novel signaling pathway for hypoxia-mediated metastasis and elucidate the underlying regulatory mechanism and functional significance of MT4-MMP in cancer metastasis.