Micro-RNA-21 regulates TGF-β-induced myofibroblast differentiation by targeting PDCD4 in tumor-stroma interaction

Int J Cancer. 2011 Apr 15;128(8):1783-92. doi: 10.1002/ijc.25506.


Transforming growth factor-β1 (TGF-β1) induces stromal fibroblast-to-myofibroblast transdifferentiation in the tumor-stroma interactive microenvironment via modulation of multiple phenotypic and functional genes, which plays a critical role in tumor progression. Up to now, the involvement of micro-RNAs (miRNAs) and their roles in TGF-β1-induced myofibroblast differentiation in tumor-stroma interaction are unclear. Using quantitative real-time RT-PCR, we demonstrated that the expression of micro-RNA-21 (miR-21) was upregulated in activated fibroblasts after treatment with TGF-β1 or conditioned medium from cancer cells. To determine the potential roles of miR-21 in TGF-β1-mediated gene regulation during myofibroblast conversion, we showed that miR-21 expression was downregulated by miR-21 inhibitor and upregulated by miR-21 mimic. Interestingly, downregulation of miR-21 with the inhibitor effectively inhibited TGF-β1-induced myofibroblast differentiation while upregulation of miR-21 with a mimic significantly promoted myofibroblast differentiation. We further demonstrated that MiR-21 directly targeted and downregulated programmed cell death 4 (PDCD4) gene, which in turn acted as a negative regulator of several phenotypic and functional genes of myofibroblasts. Taken together, these results suggested that miR-21 participated in TGF-β1-induced myofibroblast transdifferentiation in cancer stroma by targeting PDCD4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Blotting, Western
  • Cell Differentiation*
  • Cells, Cultured
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Culture Media, Conditioned / pharmacology
  • Female
  • Fetus
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism
  • Fluorescent Antibody Technique
  • Gene Expression Regulation*
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • MicroRNAs / physiology*
  • Myofibroblasts / cytology*
  • Myofibroblasts / metabolism
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • RNA, Messenger / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stromal Cells / metabolism*
  • Stromal Cells / pathology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Tumor Microenvironment


  • Apoptosis Regulatory Proteins
  • Culture Media, Conditioned
  • MIRN21 microRNA, human
  • MicroRNAs
  • PDCD4 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • Transforming Growth Factor beta