Large-scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome-scale, gain-of-function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor-suppressive characteristics in vivo. A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA-mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease.

中文翻译：

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基因组规模的筛选揭示了卵巢癌对miRNA过表达的敏感性。

上皮性卵巢癌（EOC）的大规模分子注释表明该病的病因学上存在显着的异质性。这种多样性为阻碍干预目标的发现提出了重大障碍。但是，miRNA生物发生的失活通常与晚期疾病有关。因此，miRNA活性的恢复可能代表着多种EOC癌基因型之间的共同脆弱性。为了测试这一点，我们在大范围多样的EOC细胞系中采用了基因组规模，功能获得的miRNA模拟毒性筛选方法。我们发现，所有细胞系都至少对某些miRNA模拟物有反应，但miRNA模拟物的性质会引起反应，在面板中具有高度选择性。利用这些选择性毒性概况来定义miRNA模拟物在体内具有肿瘤抑制特征的作用方式和分子反应指标。从这种分析中得出的一个机械原理是EOC对miRNA介导的细胞命运规范程序释放的敏感性，而丧失它可能是这种疾病发展的先决条件。