Functional significance of sequence variation among miR-200/205 families of miRNAs in ovarian cancer

Abstract

MicroRNAs are short non-coding RNAs that regulate large suites of target genes. A family of miRNAs known as the miR-200 is implicated in the epithelial-mesenchymal/ mesenchymal-epithelial transition (EMT/MET), a process associated with cancer metastasis. Overexpression of miR-200 family miRNAs results in the induction of MET and increased sensitivity to chemotherapeutic drugs. We demonstrated here that the molecular changes and drug sensitivities induced by overexpression of miR-200 family members in mesenchymal-like ovarian cancer cells are highly variable and correlated with sequence variation within the seed and non-seed regions of individual family members. Analysis of the functional and evolutionary significance of sequence variation within the human miRNA seed regions indicates that as little as a single nucleotide change within miRNA seed regions dramatically changes the spectrum of mRNAs regulated by the overexpressed miRNA and that additional seed nucleotide changes have no significant added effect. These findings help explain the highly conserved nature of miRNA seed regions within and across species and develop a better understanding of the evolution of miRNA mediated regulation of target mRNAs. Finally, we provide evidence for seed region/non-seed interactions in the regulation of miRNA induced changes in response to cisplatin in ovarian cancer cells. Our results provide a better understanding of miRNA mediated regulation and their potential as new therapeutic agents.