miR-125b functions as a key mediator for snail-induced stem cell propagation and chemoresistance

J Biol Chem. 2013 Feb 8;288(6):4334-45. doi: 10.1074/jbc.M112.419168. Epub 2012 Dec 19.

Abstract

Chemoresistance is a major obstacle in cancer treatment. Our previous studies have shown that miR-125b plays an important role in chemoresistance. Here we report a novel mechanism that up-regulation of miR-125b through Wnt signaling by Snail enriches cancer stem cells. Overexpression of Snail dramatically increases the expression of miR-125b through the Snail-activated Wnt/β-catenin/TCF4 axis. Snail confers chemoresistance by repressing Bak1 through up-regulation of miR-125b. Restoring the expression of Bak1 or depleting miR-125b re-sensitizes Snail-expressing cancer cells to Taxol, indicating that miR-125b is critical in Snail-induced chemoresistance. Moreover, overexpression of miR-125b significantly increases the cancer stem cell population (CD24-CD44+), while depletion of miR-125b or rescue of the expression of Bak1 increases the non-stem cell population (CD24+CD44+) in Snail-overexpressing cells. These findings strongly support that miR-125b functions as a key mediator in Snail-induced cancer stem cell enrichment and chemoresistance. This novel mechanism for Snail-induced stem cell propagation and chemoresistance may have important implications in the development of strategies for overcoming cancer cell resistance to chemotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Humans
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Paclitaxel / pharmacology
  • RNA, Neoplasm / biosynthesis*
  • RNA, Neoplasm / genetics
  • Snail Family Transcription Factors
  • Transcription Factor 4
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • BAK1 protein, human
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • MIRN125 microRNA, human
  • MicroRNAs
  • Neoplasm Proteins
  • RNA, Neoplasm
  • Snail Family Transcription Factors
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • Wnt Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • beta Catenin
  • Paclitaxel