Regulation of membrane-type 4 matrix metalloproteinase by SLUG contributes to hypoxia-mediated metastasis

Neoplasia. 2009 Dec;11(12):1371-82. doi: 10.1593/neo.91326.


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 overexpressed 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-1alpha (HIF-1alpha) induced MT4-MMP expression in human cancer cells. Activation of SLUG, a transcriptional factor regulating the EMT process of human cancers, by HIF-1alpha 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-1alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Line
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Matrix Metalloproteinase 17 / genetics*
  • Matrix Metalloproteinase 17 / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Models, Biological
  • Neoplasm Metastasis
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Snail Family Transcription Factors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transplantation, Heterologous


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • SNAI1 protein, human
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • Transcription Factors
  • Matrix Metalloproteinase 17