Mononuclear cytotrophoblasts of the human placenta proliferate rapidly, subsequently fuse and differentiate to form multinucleated syncytiotrophoblast with induction in aromatase/hCYP19A1 and chorionic gonadotropin (hCGß) expression. Using microarray analysis, we identified members of the miR-17~92 cluster and its paralogs, miR-106a~363 and miR-106b~25, that are significantly downregulated upon syncytiotrophoblast differentiation. Interestingly, miR-19b and miR-106a directly targeted hCYP19A1 expression, while miR-19b also targeted hGCM1, a transcription factor critical for mouse labyrinthine trophoblast development. Overexpression of these miRNAs impaired syncytiotrophoblast differentiation. hGCM1 knockdown decreased hCYP19A1 and hCGß expression, substantiating its important role in human trophoblast differentiation. Expression of the protooncogene, c-Myc, was increased in proliferating cytotrophoblasts, compared to differentiated syncytiotrophoblast. Moreover, c-Myc overexpression upregulated miR-17~92 and inhibited hCYP19A1 and hCGß expression. Binding of endogenous c-Myc to genomic regions upstream of the miR-17~92 and miR-106a~363 clusters in cytotrophoblasts dramatically decreased upon syncytiotrophoblast differentiation. Intriguingly, we observed higher levels of miR-106a and -19b and lower aromatase and hGCM1 expression in placentas from preeclamptic women, as compared to placentas from gestation-matched normotensive women. Our findings reveal that c-Myc-regulated members of miR-17~92 and miR-106a~363 clusters inhibit trophoblast differentiation by repressing hGCM1 and hCYP19A1 and suggest that aberrant regulation of these miRNAs may contribute to the pathogenesis of preeclampsia.

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