The c-Myc-Regulated MicroRNA-17∼92 (miR-17∼92) and miR-106a∼363 Clusters Target hCYP19A1 and hGCM1 To Inhibit Human Trophoblast Differentiation
The c-Myc-Regulated MicroRNA-17∼92 (miR-17∼92) and miR-106a∼363 Clusters Target hCYP19A1 and hGCM1 To Inhibit Human Trophoblast Differentiation
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DOI：
10.1128/mcb.01228-12
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发表时间：
2013-05-01
影响因子：
5.3
通讯作者：
Mendelson, Carole R.
中科院分区：
文献类型：
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作者：
Kumar, Premlata;Luo, Yanmin;Mendelson, Carole R.
人胎盘的单核细胞滋养层细胞在芳香酶(HCYP19A1)和绒毛膜促性腺激素(hCGβ)表达的诱导下，迅速增殖、融合和分化形成多核合体滋养层细胞。通过基因芯片分析，我们鉴定了miR-17类似于92簇的成员及其同源基因，miR-106a类似于363，miR-106b类似于25，它们在合体滋养层细胞分化过程中显著下调。有趣的是，miR-19b和miR-106a直接针对hCYP19A1的表达，而miR-19b也针对人GCM1(HGCM1)，这是一种对小鼠迷路滋养层细胞发育至关重要的转录因子。这些microRNAs(MiRNAs)的过表达会损害合体滋养层细胞的分化。HGCM1基因敲除可降低hCYP19A1和hCGβ的表达，证实其在人滋养层细胞分化中的重要作用。原癌基因c-Myc在增殖期细胞滋养层细胞中的表达高于分化的合体滋养层细胞。此外，c-Myc过表达上调miR-17与92类似，并抑制hCYP19A1和hCGβ的表达。在合体滋养层细胞分化过程中，内源性c-Myc与细胞滋养层细胞miR-17上游类似92和miR-106a类似于363簇的结合显着减少。有趣的是，我们观察到先兆子痫妇女胎盘中miR-106a和-19b的水平高于妊娠配对的正常血压妇女胎盘，芳香酶和hGCM1的表达低于妊娠配对的正常血压妇女。我们的发现表明，类似于92的miR-17和类似于363簇的miR-106a的c-Myc调控成员通过抑制hGCM1和hCYP19A1来抑制滋养细胞的分化，提示这些miRNAs的异常调控可能参与了子痫前期的发病。
Mononuclear cytotrophoblasts of the human placenta proliferate rapidly, subsequently fuse, and differentiate to form multinucleated syncytiotrophoblast with induction of aromatase (hCYP19A1) and chorionic gonadotropin (hCG beta) expression. Using microarray analysis, we identified members of the miR-17 similar to 92 cluster and its paralogs, miR-106a similar to 363 and miR-106b similar to 25, that are significantly downregulated upon syncytiotrophoblast differentiation. Interestingly, miR-19b and miR-106a directly targeted hCYP19A1 expression, while miR-19b also targeted human GCM1 (hGCM1), a transcription factor critical for mouse labyrinthine trophoblast development. Overexpression of these microRNAs (miRNAs) impaired syncytiotrophoblast differentiation. hGCM1 knockdown decreased hCYP19A1 and hCG beta expression, substantiating its important role in human trophoblast differentiation. Expression of the c-Myc proto-oncogene was increased in proliferating cytotrophoblasts compared to that in differentiated syncytiotrophoblast. Moreover, c-Myc overexpression upregulated miR-17 similar to 92 and inhibited hCYP19A1 and hCG beta expression. Binding of endogenous c-Myc to genomic regions upstream of the miR-17 similar to 92 and miR-106a similar to 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 than in placentas from gestation-matched normotensive women. Our findings reveal that c-Myc-regulated members of the miR-17 similar to 92 and miR-106a similar to 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.