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Hyperinsulinemia-induced PAX6 expression promotes endometrial epithelial cell proliferation via negatively modulating p27 signaling.
Biomedicine & Pharmacotherapy 2018 January
Polycystic ovarian syndrome (PCOS) is thought to involve hyperinsulinism (insulin resistance, IR) and high prevalence of endometrial epithelial hyperplasia, but how these two pathologies are synergistically regulated in endometrial epithelial cells remains largely unknown. Here, we report a key role for the transcription factor PAX6 in the modulation of PCOS-induced endometrial epithelial proliferation. PAX6 was significantly induced in the endometrial tissues from PCOS patients, and this induction, regulated upstream by high levels of insulin, was closely correlated to the pathogenesis of IR in endometrial epithelial cells. Overexpression of the exogenous PAX6 potentiated the insulin-elicited accumulation of S phase in endometrial epithelial cells and thereby promoted endometrial epithelial proliferation. In parallel, by using luciferase reporter and ChIP assay, we found that PAX6 directly bound to the promoter of CDKN1B gene (the gene encoding p27 protein, a negative regulator of cell cycle) and inhibited CDKN1B transcription in the insulin-stimulated endometrial epithelial cells. We conclude that excessive PAX6 expression in insulin-challenged endometrial epithelial cells may contribute to the uncontrollable endometrial epithelial proliferation. Our results also provide a mechanistic explanation for the functional link between hyperinsulinemia and p27 loss in the pathogenesis of endometrial epithelial hyperplasia in PCOS patients.
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