Abstract
The epithelial–mesenchymal transition (EMT) has recently been linked to stem cell phenotype1,2. However, the molecular mechanism underlying EMT and regulation of stemness remains elusive. Here, using genomic approaches, we show that tumour suppressor p53 has a role in regulating both EMT and EMT-associated stem cell properties through transcriptional activation of the microRNA miR-200c. p53 transactivates miR-200c through direct binding to the miR-200c promoter. Loss of p53 in mammary epithelial cells leads to decreased expression of miR-200c and activates the EMT programme, accompanied by an increased mammary stem cell population. Re-expressing miR-200c suppresses genes that mediate EMT and stemness properties3,4 and thereby reverts the mesenchymal and stem-cell-like phenotype caused by loss of p53 to a differentiated epithelial cell phenotype. Furthermore, loss of p53 correlates with a decrease in the level of miR-200c, but an increase in the expression of EMT and stemness markers, and development of a high tumour grade in a cohort of breast tumours. This study elucidates a role for p53 in regulating EMT–MET (mesenchymal–epithelial transition) and stemness or differentiation plasticity, and reveals a potential therapeutic implication to suppress EMT-associated cancer stem cells through activation of the p53–miR-200c pathway.
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Change history
15 November 2011
In the version of this article initially published online and in print, Figs 2b and 4a contained panels that did not match those in Supplementary Fig. S5. These errors have been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank R. A. Weinberg and S. Mani for providing HMEC and HMEC-Snail cells, E. Flores for providing the p53 knockout mice and J. Lang for technical assistance. This study was supported by RO1 CA109311, PO1 CA099031, Breast SPORE P50 CA116199, Cancer Center Support Grant CA16672, the National Breast Cancer Foundation, Inc., the Breast Cancer Research Foundation, the Sister Institution Fund of China Medical University Hospital and MD Anderson Cancer Center, the National Science Council of Taiwan (grants NSC-96-3111-B-039, NSC97-2917-I-564-107 and NSC-2632-B-039) and the Cancer Research Center for Excellence, Taiwan Department of Health (grant DOH99-TD-C-111-005 to M-C. H.). In memoriam, Ms. Serena Lin-Guo for her courageous fight against cancer.
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C-J.C., C-H.C. and M-C.H. designed and conceived the study. C-J.C. and C-H.C. performed the experiments and wrote the manuscript. W.X. performed and analysed the immunohistochemistry experiments. Y.X., S.K.R. and D.Y. performed the miRNA in situ hybridization experiments. J-Y.Y., C-W.L., W-H.Y., H-H.L. and M.L. helped with the biochemical experiments. C-T.C. and H.J.L. helped with the animal experiments. H.J.L. edited the manuscript.
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Chang, CJ., Chao, CH., Xia, W. et al. p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 13, 317–323 (2011). https://doi.org/10.1038/ncb2173
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DOI: https://doi.org/10.1038/ncb2173
