期刊
NEOPLASIA
卷 11, 期 12, 页码 1371-U148出版社
ELSEVIER SCIENCE INC
DOI: 10.1593/neo.91326
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资金
- National Science Council [96-2314-B-075-013, 97-2314-B-010-003, 97-2320-B-010-029, 98-2314-B-075-033]
- National Research Program for GenomicMedicine [DOH97-TD-G-111-038, DOH98-TD-G-111-027]
- Taipei Veterans General Hospital [VGH 97-C1-032 97-ER2-008, 98-C1-50, 98-ER-008]
- Ministry of Education, Aim for the Top University Plan [97-A-C-T510, 97-A-C-T509, 97-A-C-D104]
- National Health Research Institutes [NHRI-EX-97-9611BI]
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.
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