Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization

Nat Med. 2011 Aug 7;17(9):1101-8. doi: 10.1038/nm.2401.

Abstract

Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Mass Spectrometry
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / metabolism*
  • Microarray Analysis
  • Neoplasm Metastasis / physiopathology*
  • Statistics, Nonparametric
  • Vesicular Transport Proteins / metabolism*

Substances

  • Cadherins
  • MIRN200 microRNA, human
  • MicroRNAs
  • Sec23a protein, mouse
  • Vesicular Transport Proteins

Associated data

  • GEO/GSE19631