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.