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Smad3 regulates E-cadherin via miRNA-200 pathway

Oncogene volume 31, pages 3051–3059 (2012)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr GJ Goodall for kindly providing the DNA constructs. This work was supported by the National Research Foundation grant funded by the Korea government (MEST) to S Hong (KRF-2008-313-C00676 and no. 2009-0081756), JY Cha and SM Ahn (no. 2009-0081789) and by the generous funding from the department of gastroenterology, Gachon University Gil Hospital to D Park.

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Author notes

  1. S-M Ahn, J-Y Cha and J Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Medicine, Laboratory of Cancer Cell Biology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea

    S-M Ahn, J-Y Cha, J Kim, D Kim, H T H Trang, Y-M Kim, Y-H Cho & S Hong

  2. Department of Translational Medicine, Gachon University Gil Hospital, Incheon, Korea

    S-M Ahn

  3. Department of Gastroenterology, Gachon University Gil Hospital, Incheon, Korea

    D Park

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  1. S-M Ahn
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Correspondence to D Park or S Hong.

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Ahn, SM., Cha, JY., Kim, J. et al. Smad3 regulates E-cadherin via miRNA-200 pathway. Oncogene 31, 3051–3059 (2012). https://doi.org/10.1038/onc.2011.484

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