Epigenetic silencing of ITGA2 by MiR-373 promotes cell migration in breast cancer

PLoS One. 2015 Aug 10;10(8):e0135128. doi: 10.1371/journal.pone.0135128. eCollection 2015.

Abstract

The loss of ITGA2 plays an important role in cancer metastasis in several solid cancers. However, the molecular mechanism of ITGA2 loss in primary cancers remains unclear. In this study, we found that a lower ITGA2 protein level was observed in breast cancers compared to adjacent non-cancerous breast tissues. Interestingly, the reduction degree of ITGA2 at the protein level was far more than that at the mRNA level. We further showed that the translation of ITGA2 mRNA was directly inhibited by miR-373 through binding to ITGA2-3'UTR. Silencing of ITGA2 detached cell-cell interactions, induced the deploymerization of stress fiber F-actin and stimulated cancer cell migration, similar to the effect of miR-373 over-expression. The co-expression of ITGA2, not ITGA2-3'UTR, could abrogate miR-373-induced cancer cell migration because that the expression of ITGA2-3'UTR was inhibited by co-transfected miR-373. ITGA2 protein level was inversely associated with miR-373 level in breast cancers (r = -0.663, P<0.001). 73.33% of breast cancer patients with high miR-373 and low ITGA2 expression exhibited the lymph node-positive metastases. Together, our results show that epigenetic silencing of ITGA2 by miR-373 stimulates breast cancer migration, and miR-373high/ITGA2low may be as a prognosis biomarker for breast cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions*
  • Actins / chemistry
  • Actins / genetics
  • Actins / metabolism
  • Adult
  • Aged
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Movement
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing*
  • Genes, Reporter
  • Humans
  • Integrin alpha2 / genetics*
  • Integrin alpha2 / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • Lymphatic Metastasis
  • MCF-7 Cells
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Middle Aged
  • Signal Transduction

Substances

  • 3' Untranslated Regions
  • Actins
  • ITGA2B protein, human
  • Integrin alpha2
  • MIRN373 microRNA, human
  • MicroRNAs
  • Luciferases

Grant support

This work was supported by the National Natural Science Foundation of China (81071618, 81272285), Zhujiang Science & Technology New Star Projects of Guangzhou (2011J2200042) and the Natural Science Foundation of Guangdong Province of China (S2012010008882) and the R&D plan of Guangzhou and Panyu (2011B031800043, 2011-Z-03-29). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.