Abstract
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 30 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3985-4000 |
| Number of pages | 16 |
| Journal | Cancer Research |
| Volume | 81 |
| Issue number | 15 |
| DOIs | |
| State | Published - Aug 1 2021 |
Funding
The authors are grateful to Drs. Gallois-Montbrun and Mulder for providing Ago2 KO cell lines. This work was funded by grant R35CA197450 (to M.E. Peter), R50CA221848 (to E.T. Bartom), and Ovarian Cancer Research Alliance grant number 458788 (to K.P. Nephew, D. Matei, and M.E. Peter). M. Patel reports a patent for 15/900,392 pending. E.T. Bartom reports grants from NIH during the conduct of the study and grants from NIH outside the submitted work. D. Matei reports grants from OCRA during the conduct of the study. A.E. Murmann reports a patent for U.S. Serial No. 62/821,776 pending, a patent for U.S. Serial No. 2/821,782 pending, and a patent for U.S. Serial No. 15/900,392 pending. E. Lengyel reports grants from AbbVie and grants from Arsenal Bioscience outside the submitted work. M.E. Peter reports grants from National Institutes of Health and grants from Ovarian Cancer Research Alliance during the conduct of the study; in addition, M.E. Peter has a patent for U.S. Serial No. 62/821,776 pending, a patent for U.S. Serial No. 2/821,782 pending, and a patent for U.S. Serial No. 15/900,392 pending. No disclosures were reported by the other authors.
ASJC Scopus subject areas
- Oncology
- Cancer Research
