MicroRNA-221 targeting PI3-K/Akt signaling axis induces cell proliferation and BCNU resistance in human glioblastoma

Neuropathology. 2014 Oct;34(5):455-64. doi: 10.1111/neup.12129. Epub 2014 Apr 30.

Abstract

MicroRNAs (miRNAs) are short regulatory RNAs that negatively regulate protein biosynthesis at the post-transcriptional level and participate in the pathogenesis of different types of human cancers, including glioblastoma. In particular, the levels of miRNA-221 are overexpressed in many cancers and miRNA-221 exerts its functions as an oncogene. Nevertheless, the roles of miRNA-221 in carmustine (BCNU)-resistant glioma cells have not been totally elucidated. In the present study, we explored the effects of miRNA-221 on BCNU-resistant glioma cells and the possible molecular mechanisms by which miRNA-221 mediated the cell proliferation, survival, apoptosis and BCNU resistance were investigated. We found that miR-221 was overexpressed in glioma cells, including BCNU-resistant cells. Moreover, we found that miR-221 regulated cell proliferation and BCNU resistance in glioma cells. Overexpression of miR-221 led to cell survival and BCNU resistance and reduced cell apoptosis induced by BCNU, whereas knockdown of miR-221 inhibited cell proliferation and prompted BCNU sensitivity and cell apoptosis. Further investigation revealed that miR-221 down-regulated PTEN and activated Akt, which resulted in cell survival and BCNU resistance. Overexpression of PTEN lacking 3'UTR or PI3-K/Akt specific inhibitor wortmannin attenuated miR-221-mediated BCNU resistance and prompted cell apoptosis. We propose that miR-221 regulated cell proliferation and BCNU resistance in glioma cells by targeting PI3-K/PTEN/Akt signaling axis. Our findings may provide a new potential therapeutic target for treatment of glioblastoma.

Keywords: Akt; BCNU; PTEN; glioma; miR-221.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / pharmacology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Carmustine / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction

Substances

  • Antineoplastic Agents, Alkylating
  • MIRN221 microRNA, human
  • MicroRNAs
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Carmustine