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首页> 外文期刊>Neoplasia: an international journal for oncology research >The Oncogenic Roles of DICER1 RNase IIIb Domain Mutations in Ovarian Sertoli-Leydig Cell Tumors
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The Oncogenic Roles of DICER1 RNase IIIb Domain Mutations in Ovarian Sertoli-Leydig Cell Tumors

机译：Dicer1 RNase IIIB结构域突变在卵巢Sertoli-Leydig细胞肿瘤中的致癌作用

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DICER1, an endoribonuclease required for microRNA (miRNA) biogenesis, is essential for embryogenesis and the development of many organs including ovaries. We have recently identified somatic hotspot mutations in RNase IIIb domain of DICER1 in half of ovarian Sertoli-Leydig cell tumors, a rare class of sex-cord stromal cell tumors in young women. These hotspot mutations lost IIIb cleavage activity of DICER1 in vitro and failed to produce 5p-derived miRNAs in mouse Dicer1-null ES cells. However, the oncogenic potential of these hotspot DICER1 mutations has not been studied. Here, we further revealed that the global expression of 5p-derived miRNAs was dramatically reduced in ovarian Sertoli-Leydig cell tumors carrying DICER1 hotspot mutations compared with those without DICER1 hotspot mutation. The miRNA production defect was associated with the deregulation of genes controlling cell proliferation and the cell fate. Using an immortalized human granulosa cell line, SVOG3e, we determined that the D1709N-DICER1 hotspot mutation failed to produce 5p-derived miRNAs, deregulated the expression of several genes that control gonadal differentiation and cell proliferation, and promoted cell growth. Re-expression of let-7 significantly inhibited the growth of D1709N-DICER1 SVOG3e cells, accompanied by the suppression of key regulators of cell cycle control and ovarian gonad differentiation. Taken together, our data revealed that DICER1 hotspot mutations cause systemic loss of 5p-miRNAs that can both drive pseudodifferentiation of testicular elements and cause oncogenic transformation in the ovary.
机译：Dicer1，MicroRNA（miRNA）生物生物所需的内衣核酸酶，对于胚胎发生和许多包括卵巢的开发至关重要。我们最近鉴定了卵巢塞托洛里德细胞肿瘤的一半Dicer1的RNase IIIB域中的体细胞热点突变，是年轻女性的珍稀类的性脐带基质细胞肿瘤。这些热点突变在体外失去了Dicer1的IIIB裂解活性，并且在小鼠Dicer1-Null ES细胞中未能产生5ps衍生的miRNA。然而，尚未研究这些热点Dicer1突变的致癌潜力。在这里，我们进一步揭示，与没有Dicer1热点突变的人相比，卵巢塞托洛尔-Leydig细胞肿瘤中，在卵巢塞托洛丽 - leydig细胞肿瘤中显着降低了5P衍生的miRNA的全局表达。 MiRNA生产缺陷与控制细胞增殖和细胞命运的基因的放松管制有关。使用永生化的人颗粒细胞系SVOG3E，我们确定D1709N-DICER1热点突变未能产生5ps衍生的miRNA，Deerocoation对控制性腺分化和细胞增殖的几种基因的表达，并促进细胞生长。重新表达Let-7显着抑制D1709N-Dicer1 Svog3e细胞的生长，伴随着细胞周期控制和卵巢性腺分化的关键调节剂的抑制。我们的数据集中在一起揭示了Dicer1热点突变导致5p-miRNA的全身损失，其可以驱动睾丸元素的假细胞化并导致卵巢中的致癌转化。

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