miR-222 attenuates cisplatin-induced cell death by targeting the PPP2R2A/Akt/mTOR Axis in bladder cancer cells

J Cell Mol Med. 2016 Mar;20(3):559-67. doi: 10.1111/jcmm.12760. Epub 2016 Jan 22.


Increased miR-222 levels are associated with a poor prognosis in patients with bladder cancer. However, the role of miR-222 remains unclear. In the present study, we found that miR-222 enhanced the proliferation of both the T24 and the 5637 bladder cancer cell lines. Overexpression of miR-222 attenuated cisplatin-induced cell death in bladder cancer cells. miR-222 activated the Akt/mTOR pathway and inhibited cisplatin-induced autophagy in bladder cancer cells by directly targeting protein phosphatase 2A subunit B (PPP2R2A). Blocking the activation of Akt with LY294002 or mTOR with rapamycin significantly prevented miR-222-induced proliferation and restored the sensitivity of bladder cancer cells to cisplatin. These findings demonstrate that miR-222 modulates the PPP2R2A/Akt/mTOR axis and thus plays a critical role in regulating proliferation and chemotherapeutic drug resistance. Therefore, miR-222 may be a novel therapeutic target for bladder cancer.

Keywords: bladder cancer; cisplatin; microRNA-222.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Antineoplastic Agents / pharmacology*
  • Base Sequence
  • Binding Sites
  • Cell Death / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / physiology*
  • Protein Phosphatase 2 / genetics*
  • Protein Phosphatase 2 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Urinary Bladder Neoplasms


  • 3' Untranslated Regions
  • Antineoplastic Agents
  • MIRN222 microRNA, human
  • MicroRNAs
  • PPP2R2A protein, human
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Protein Phosphatase 2
  • Cisplatin