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首页> 外文期刊>Cell discovery. >Regulation of hnRNPA1 by microRNAs controls the miR-18a–K-RAS axis in chemotherapy-resistant ovarian cancer
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Regulation of hnRNPA1 by microRNAs controls the miR-18a–K-RAS axis in chemotherapy-resistant ovarian cancer

机译：微小RNA对hnRNPA1的调控控制了化疗耐药性卵巢癌的miR-18a– K-RAS 轴

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The regulation of microRNA (miRNA) biogenesis, function and degradation involves a range of mechanisms, including interactions with RNA-binding proteins. The potential contribution of regulatory miRNAs to the expression of these RNA interactor proteins that could control other miRNAs expression is still unclear. Here we demonstrate a regulatory circuit involving oncogenic and tumor-suppressor miRNAs and an RNA-binding protein in a chemotherapy-resistant ovarian cancer model. We identified and characterized miR-15a-5p and miR-25-3p as negative regulators of hnRNPA1 expression, which is required for the processing of miR-18a-3p, an inhibitor of the K-RAS oncogene. The inhibition of miR-25-3p and miR-15a-5p decreased the proliferation, motility, invasiveness and angiogenic potential and increased apoptosis when combined with docetaxel. Alteration of this regulatory circuit causes poor overall survival outcome in ovarian cancer patients. These results highlight miR-15a-5p and miR-25-3p as key regulators of miR-18a-3p expression and its downstream target K-RAS , through direct modulation of hnRNPA1 expression. Our results demonstrate the therapeutic potential of inhibiting miR-25-3p and miR-15a-5p and the use of miR-18a-3p/KRAS ratio as a prominent outcome prognostic factor.
机译：microRNA（miRNA）生物发生，功能和降解的调控涉及多种机制，包括与RNA结合蛋白的相互作用。尚不清楚调节性miRNA对这些可控制其他miRNA表达的RNA相互作用蛋白表达的潜在作用。在这里，我们证明了在化疗耐药的卵巢癌模型中涉及致癌和抑癌miRNA和RNA结合蛋白的调控电路。我们鉴定并确定了miR-15a-5p和miR-25-3p为hnRNPA1表达的负调节剂，这是处理miR-18a-3p（K-RAS癌基因的抑制剂）所必需的。与多西他赛联合使用时，对miR-25-3p和miR-15a-5p的抑制作用会降低其增殖，运动性，侵袭性和血管生成潜能，并增加细胞凋亡。该调节回路的改变导致卵巢癌患者的总体生存结果差。这些结果强调了通过直接调节hnRNPA1表达，miR-15a-5p和miR-25-3p是miR-18a-3p表达及其下游目标K-RAS的关键调控因子。我们的结果证明了抑制miR-25-3p和miR-15a-5p的治疗潜力以及使用miR-18a-3p / KRAS比作为重要的预后因素。

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