MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma

Mol Cancer. 2010 Sep 2:9:229. doi: 10.1186/1476-4598-9-229.

Abstract

Background: MiR-221 and miR-222 (miR-221/222) are frequently up-regulated in various types of human malignancy including glioblastoma. Recent studies have reported that miR-221/222 regulate cell growth and cell cycle progression by targeting p27 and p57. However the underlying mechanism involved in cell survival modulation of miR-221/222 remains elusive.

Results: Here we showed that miR-221/222 inhibited cell apoptosis by targeting pro-apoptotic gene PUMA in human glioma cells. Enforced expression of miR-22/222 induced cell survival whereas knockdown of miR-221/222 rendered cells to apoptosis. Further, miR-221/222 reduced PUMA protein levels by targeting PUMA-3'UTR. Introducing PUMA cDNA without 3'UTR abrogated miR-221/222-induced cell survival. Notably, knockdown of miR-221/222 induces PUMA expression and cell apoptosis and considerably decreases tumor growth in xenograft model. Finally, there was an inverse relationship between PUMA and miR-221/222 expression in glioma tissues.

Conclusion: To our knowledge, these data indicate for the first time that miR-221/222 directly regulate apoptosis by targeting PUMA in glioblastoma and that miR-221/222 could be potential therapeutic targets for glioblastoma intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Blotting, Northern
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival / physiology
  • Female
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / therapy*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • In Vitro Techniques
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • NIH 3T3 Cells
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • MIRN221 microRNA, human
  • MIRN221 microRNA, mouse
  • MIRN222 microRNA, human
  • MIRN222 microRNA, mouse
  • MicroRNAs
  • Proto-Oncogene Proteins