p53 regulates epithelial-mesenchymal transition (EMT) and stem cell properties through modulating miRNAs

Epithelial mechenchymal transition (EMT) has recently been linked to stem cell phenotype1, 2. However, the molecular mechanism involving regulation of EMT and stemness remains elusive. Here, using genomic approaches, we discovered that tumor suppressor p53 plays a role in regulating both EMT and EMT-associated stem cell properties through transcriptional activation of 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 EMT program, accompanied by increased mammary stem cell population. Re-expressing miR-200c suppresses genes that mediate EMT and stemness properties3, 4 and thereby reverts mesenchymal and stem cell-like phenotype caused by loss of p53 to differentiated epithelial cell phenotype. Furthermore, loss of p53 negatively correlates with miR-200c level but positively with increased expression of EMT and stemness markers as well as high tumor grade in a cohort of breast tumors. Together, this study elucidates a role of p53 in regulating EMT-MET (mechenchymal epithelial transition) and stemness or differentiation plasticity and reveals a potential therapeutic implication to suppress EMT associated-cancer stem cells through activation of p53-miR-200c pathway.