Downregulation of reversion-inducing cysteine-rich protein with Kazal motifs in malignant melanoma: inverse correlation with membrane-type 1-matrix metalloproteinase and tissue inhibitor of metalloproteinase 2

Melanoma Res. 2014 Feb;24(1):32-9. doi: 10.1097/CMR.0000000000000039.


The invasive phenotype of many tumors is associated with an imbalance between the matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and the membrane-anchored reversion-inducing cysteine-rich protein with Kazal motifs (RECK). RECK inhibits MMP-2, MMP-9, and MT1-MMP, and has been linked to patient survival and better prognosis in several types of tumors. However, despite the wide implication of these MMPs in melanoma establishment and progression, the role of RECK in this type of tumor is still unknown. Here, we analyzed the expression of RECK, TIMP1, TIMP2, TIMP3, MT1MMP, MMP2, and MMP9 in two publicly available melanoma microarray datasets and in a panel of human melanoma cell lines. We found that RECK is downregulated in malignant melanoma, accompanied by upregulation of MT1MMP and TIMP2. In both datasets, we observed that the group of samples displaying higher RECK levels show lower median expression levels of MT1MMP and TIMP2 and higher levels of TIMP3. When tested in a sample-wise manner, these correlations were statistically significant. Inverse correlations between RECK, MT1MMP, and TIMP2 were verified in a panel of human melanoma cell lines and in a further reduced model that includes a pair of matched primary tumor-derived and metastasis-derived cell lines. Taken together, our data indicate a consistent correlation between RECK, MT1MMP, and TIMP2 across different models of clinical samples and cell lines and suggest evidence of the potential use of this subset of genes as a gene signature for diagnosing melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Down-Regulation
  • GPI-Linked Proteins / biosynthesis*
  • GPI-Linked Proteins / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Matrix Metalloproteinase 14 / biosynthesis*
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 2 / biosynthesis
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics
  • Melanoma / enzymology
  • Melanoma / genetics*
  • Melanoma / metabolism*
  • Phenotype
  • Prognosis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-2 / biosynthesis*
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Tissue Inhibitor of Metalloproteinase-3 / biosynthesis
  • Tissue Inhibitor of Metalloproteinase-3 / genetics


  • GPI-Linked Proteins
  • RECK protein, human
  • RNA, Messenger
  • TIMP1 protein, human
  • TIMP2 protein, human
  • TIMP3 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-3
  • Tissue Inhibitor of Metalloproteinase-2
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • MMP14 protein, human
  • Matrix Metalloproteinase 14