WAVE3, an actin remodeling protein, is regulated by the metastasis suppressor microRNA, miR-31, during the invasion-metastasis cascade

Int J Cancer. 2011 Sep 15;129(6):1331-43. doi: 10.1002/ijc.25793. Epub 2011 Mar 22.

Abstract

WAVE3, an actin cytoskeleton remodeling protein, is highly expressed in advanced stages of breast cancer and influences tumor cell invasion. Loss of miR-31 has been associated with cancer progression and metastasis. Here, we show that the activity of WAVE3 to promote cancer cell invasion is regulated by miR-31. An inverse correlation was demonstrated between expression levels of WAVE3 and miR-31 in invasive versus noninvasive breast cancer cell lines. miR-31 directly targeted the 3'-UTR of the WAVE3 mRNA and inhibited its expression in the invasive cancer cells, i.e., miR-31-mediated down-regulation of WAVE3 resulted in a significant reduction in the invasive phenotype of cancer cells. This relationship was specific to the loss of WAVE3 expression because re-expression of a miR-31-resistant form of WAVE3 reversed miR-31-mediated inhibition of cancer cell invasion. Furthermore, expression of miR-31 correlates inversely with breast cancer progression in humans, where an increase in expression of miR-31 target genes was observed as the tumors progressed to more aggressive forms. In conclusion, a novel mechanism for the regulation of WAVE3 expression in cancer cells has been identified, which controls the invasive properties of cancer cells. The study also identifies a critical role for WAVE3, downstream of miR-31, in the invasion-metastasis cascade.

Publication types

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

MeSH terms

  • 3' Untranslated Regions
  • Breast Neoplasms / genetics*
  • Cell Line, Tumor
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / physiology*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis / prevention & control
  • Up-Regulation
  • Wiskott-Aldrich Syndrome Protein Family / genetics*

Substances

  • 3' Untranslated Regions
  • MIRN200 microRNA, human
  • MIRN31 microRNA, human
  • MicroRNAs
  • WASF3 protein, human
  • Wiskott-Aldrich Syndrome Protein Family