Reversal of EMT by regulation of miR-200c through treatment of metformin and resveratrol in DEN-induced rat HCC.

Epithelial mesenchymal transition (EMT) is a powerful process in which epithelial cells undergo a transcriptional reprogramming and morphological changes that acquire a mesenchymal phenotype which have reported to enhance the migratory properties. The aberrant expression of miR-200 family was reported to play a role in cancer and EMT. The metastatic inhibitory role of the miR-200 family is strongly associated with a pathologic EMT. In the present study, we compared the expression levels of miR-200c between Doxorubicin+ Resveratrol+ Metformin (Dox+Res+Met) and Dox resistant DEN-induced rat HCC, and investigated whether the treatment of rats with resveratrol and metformin could affect the expression of miR-200c. The expression level of miR-200c was significantly down-regulated in Dox-resistant rats that showed EMT characteristics such as lower expression of epithelial marker E-cadherin, and higher expression of mesenchymal markers such as vimentin and ZEB1 which may correlate to Dox resistance. Overexpression of miR-200c in resistant HCC rats restored their sensitivities to Dox, leading to acquisition of mesenchymal-epithelial transition-like phenotypes, including up-regulation of E-cadherin, down-regulation of ZEB1 and Vimentin versus Dox-treated group. These results provided experimental evidence that resveratrol and metformin could function as miRNA regulators leading to the reversal of EMT phenotype, which is likely to be important for designing novel therapies for HCC.