Sequence diverse miRNAs converge to induce mesenchymal-to-epithelial transition in ovarian cancer cells through direct and indirect regulatory controls

• Published in: Cancer letters 2019-09, Vol.459, p.168-175
• Main Authors: Zhang, Mengnan, Jabbari, Neda, Satpathy, Minati, Matyunina, Lilya V., Wang, Yuehua, McDonald, L. DeEtte, McDonald, John F.
• Format: Article
• Language: English
• Subjects: Convergent evolution; Epithelial-to-mesenchymal transition (EMT); Gene expression; Gene regulation; Mesenchymal-to-epithelial transition (MET); Mesenchyme; Metastasis; Microarray gene expression; MicroRNAs; miRNA; Morphology; Ovarian cancer; Overexpression; Phylogeny; Proteins; Software; Wnt protein
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.05.039

Epithelial-to-mesenchymal transition (EMT) has been shown to be similarly regulated by multiple miRNAs, some displaying little or no sequence identity. While alternate models have been proposed to explain the functional convergence of sequence divergent miRNAs, little experimental evidence exists to elucidate the underlying mechanisms involved. Representative members of the miR-200 family of miRNAs and the sequence divergent miR-205 miRNA were independently over expressed in mesenchymal-like ovarian cancer (OC) cells resulting in mesenchymal-to-epithelial transition (MET). The miR-205 and the miR-200 family of miRNAs were found to coordinately induce MET in mesenchymal-like OC cells by affecting both direct and indirect changes in the expression of genes previously associated with EMT/MET. Only two direct targets of these miRNAs (ZEB 1 and WNT5A) are commonly down regulated in response to over-expression of miR-205 and/or the miR-200 family of miRNAs. Down-regulation of these genes, alone or in combination, only partially recapitulates the changes induced by the miRNAs indicating an additional contribution of indirect changes regulated by the miRNAs. Combined gene expression analyses and phylogenetic comparisons suggest an evolutionarily more recent involvement of miR-205 in the EMT/MET process. •Sequence-divergent miRNAs can induce mesenchymal-to-epithelial transition (MET).•Sequence-divergent miR-205 and the miR-200 family of miRNAs induce MET.•Only 3.3% of genes induced in common by these miRNAs are direct regulatory targets.•Knockdown of MET genes targeted in common by these miRNAs induces only partial MET.•The miR-200 family's involvement in MET evolutionarily predates that of miR-205.