Trail resistance induces epithelial-mesenchymal transition and enhances invasiveness by suppressing PTEN via miR-221 in breast cancer

PLoS One. 2014 Jun 6;9(6):e99067. doi: 10.1371/journal.pone.0099067. eCollection 2014.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis of cancer cells and is verified effective to various cancers. However, a variety of breast cancer cell lines are resistant to TRAIL and the mechanisms of resistance are largely unknown. In our present experiment, we successfully utilized breast cancer cell line MDA-MB-231 to establish TRAIL-resistant cell line. We found resistance to TRAIL could induce epithelial-mesenchymal transition (EMT) and enhance invasiveness. We further demonstrated PTEN was down-regulated in TRAIL-resistant cells. Silencing miR-221, PTEN expression was up-regulated, the process of EMT could be reversed, and the ability of migration and invasion were correspondingly weakened. We also demonstrated knockdown of miR-221 could reverse resistance to TRAIL partially by targeting PTEN. Our findings suggest that resistance to TRAIL could induce EMT and enhance invasiveness by suppressing PTEN via miR-221. Re-expression of miR-221 or targeting PTEN might serve as potential therapeutic approaches for the treatment of Trail-resistant breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Breast / metabolism
  • Breast / pathology*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Down-Regulation
  • Epithelial-Mesenchymal Transition*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / genetics*
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • PTEN Phosphohydrolase / genetics*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*

Substances

  • MIRN122 microRNA, human
  • MicroRNAs
  • TNF-Related Apoptosis-Inducing Ligand
  • PTEN Phosphohydrolase
  • PTEN protein, human

Grants and funding

This work was supported by National Natural Science Foundation of China (No. 81072150; No. 81172529; No. 81272903) and Shandong Science and Technology Development Plan (No. 2012GZC22115). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.