The ratio of toxic-to-nontoxic microRNAs predicts platinum sensitivity in ovarian cancer

Published on Jun 15, 2021in Cancer Research9.727
· DOI :10.1158/0008-5472.CAN-21-0953
Monal Patel8
Estimated H-index: 8
(NU: Northwestern University),
Yinu Wang8
Estimated H-index: 8
(NU: Northwestern University)
+ 6 AuthorsMarcus E. Peter92
Estimated H-index: 92
(NU: Northwestern University)
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 microRNAs (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 (RISC) complex and targets complementary short seed matches in the 39 untranslated region of mRNAs. Toxic 6mer seeds, which target genes critical for cancer cell survival, have been found in tumor suppressive miRNAs. Many small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) 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 ovarian cancer patients 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.
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