Smad3 regulates E-cadherin via miRNA-200 pathway

Oncogene. 2012 Jun 21;31(25):3051-9. doi: 10.1038/onc.2011.484. Epub 2011 Oct 24.


To identify potential microRNA (miRNA) links between Smad3, a mediator of TGF-β (transforming growth factor-β) signaling, and E-cadherin, we characterized the miRNA profiles of two gastric cancer cell lines: SNU484-LPCX, which does not express Smad3, and SNU484-Smad3, in which Smad3 is overexpressed. We found that among differentially expressed miRNAs, miR-200 family members are overexpressed in SNU484-Smad3 cells. Subsequent studies, including analysis of the effects of silencing Smad3 in SNU484-Smad3 cells and a luciferase reporter assay, revealed that Smad3 directly binds to a Smad-binding element located in the promoter region of miR-200b/a, where it functions as a transcriptional activator. TGF-β did not affect the regulatory role of Smad3 in transcription of miR-200 and expression of epithelial-mesenchymal transition markers. We conclude that Smad3 regulates, at the transcriptional level, miR-200 family members, which themselves regulate ZEB1 and ZEB2, known transcriptional repressors of E-cadherin, at the posttranscriptional level in a TGF-β-independent manner. This represents a novel link between Smad3 and posttranscriptional regulation by miRNAs in epithelial-mesenchymal transition in gastric cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / metabolism*
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / metabolism
  • Signal Transduction*
  • Smad3 Protein / metabolism*
  • Stomach Neoplasms / metabolism*
  • Transforming Growth Factor beta / metabolism


  • Cadherins
  • MIRN200 microRNA, human
  • MicroRNAs
  • SMAD3 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta