The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer.
The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer.
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DOI：
10.1158/0008-5472.can-21-0953
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发表时间：
2021-08-01
期刊：
影响因子：
11.2
通讯作者：
Peter ME
中科院分区：
文献类型：
--
作者：
Patel M;Wang Y;Bartom ET;Dhir R;Nephew KP;Matei D;Murmann AE;Lengyel E;Peter ME
这些发现表明，携带有毒和无毒6聚体种子的miRNA的平衡有助于卵巢癌中的铂类耐药。卵巢癌仍然是影响女性的最致命的妇科恶性肿瘤之一，对铂的耐药性的发展仍然是实现治愈的主要障碍。已确定多种机制可导致铂类耐药。许多miRNA与卵巢癌的铂敏感性和耐药性有关。miRNA的活性主要发生在其种子序列位于2-7/8位的miRNA的引导链加载到RNA诱导沉默复合物（RISC）中并靶向mRNA的3′非翻译区中的互补短种子匹配时。毒性6聚体种子，靶向对癌细胞存活至关重要的基因，已在肿瘤抑制miRNA中发现。许多siRNA和短发夹RNA（shRNA）也可以通过毒性种子杀死癌细胞，其中毒性最大的是携带富含G的6聚体种子序列。我们在这里表明，用铂处理卵巢癌细胞导致携带毒性6聚体种子的RISC结合的miRNA增加，而使用无毒种子的miRNA减少。铂耐受细胞没有表现出这种毒性变化，但保留了对携带毒性6聚体种子的siRNA介导的细胞死亡的敏感性。对卵巢癌患者肿瘤中RISC结合的miRNAs的分析显示，具有毒性与无毒种子的miRNAs之间的比率可预测治疗结果。将6聚体种子毒性概念应用于癌症相关miRNA提供了一个新的框架，用于理解和预测癌症治疗反应。这些发现表明，携带有毒和无毒6聚体种子的miRNA的平衡有助于卵巢癌中的铂类耐药。
These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer. Ovarian cancer remains one of the deadliest gynecologic malignancies affecting women, and development of resistance to platinum remains a major barrier to achieving a cure. Multiple mechanisms have been identified to confer platinum resistance. Numerous miRNAs have been linked to platinum sensitivity and resistance in ovarian cancer. miRNA activity occurs mainly when the guide strand of the miRNA, with its seed sequence at position 2–7/8, is loaded into the RNA-induced silencing complex (RISC) and targets complementary short seed matches in the 3′ untranslated region of mRNAs. Toxic 6mer seeds, which target genes critical for cancer cell survival, have been found in tumor-suppressive miRNAs. Many siRNAs and short hairpin RNAs (shRNA) can also kill cancer cells via toxic seeds, the most toxic of which carry G-rich 6mer seed sequences. We showed here that treatment of ovarian cancer cells with platinum led to increased RISC-bound miRNAs carrying toxic 6mer seeds and decreased miRNAs with nontoxic seeds. Platinum-tolerant cells did not exhibit this toxicity shift but retained sensitivity to cell death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in tumors from patients with ovarian cancer revealed that the ratio between miRNAs with toxic versus nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses. These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer.