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The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity 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 sensitivit...

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Autores principales: Patel, Monal, Wang, Yinu, Bartom, Elizabeth T., Dhir, Rohin, Nephew, Kenneth P., Matei, Daniela, Murmann, Andrea E., Lengyel, Ernst, Peter, Marcus E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338879/
https://www.ncbi.nlm.nih.gov/pubmed/34224372
http://dx.doi.org/10.1158/0008-5472.CAN-21-0953
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author Patel, Monal
Wang, Yinu
Bartom, Elizabeth T.
Dhir, Rohin
Nephew, Kenneth P.
Matei, Daniela
Murmann, Andrea E.
Lengyel, Ernst
Peter, Marcus E.
author_facet Patel, Monal
Wang, Yinu
Bartom, Elizabeth T.
Dhir, Rohin
Nephew, Kenneth P.
Matei, Daniela
Murmann, Andrea E.
Lengyel, Ernst
Peter, Marcus E.
author_sort Patel, Monal
collection PubMed
description 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. SIGNIFICANCE: These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer.
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spelling pubmed-83388792022-02-01 The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer Patel, Monal Wang, Yinu Bartom, Elizabeth T. Dhir, Rohin Nephew, Kenneth P. Matei, Daniela Murmann, Andrea E. Lengyel, Ernst Peter, Marcus E. Cancer Res Genome and Epigenome 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. SIGNIFICANCE: These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer. American Association for Cancer Research 2021-08-01 2021-06-15 /pmc/articles/PMC8338879/ /pubmed/34224372 http://dx.doi.org/10.1158/0008-5472.CAN-21-0953 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Genome and Epigenome
Patel, Monal
Wang, Yinu
Bartom, Elizabeth T.
Dhir, Rohin
Nephew, Kenneth P.
Matei, Daniela
Murmann, Andrea E.
Lengyel, Ernst
Peter, Marcus E.
The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer
title The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer
title_full The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer
title_fullStr The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer
title_full_unstemmed The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer
title_short The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer
title_sort ratio of toxic-to-nontoxic mirnas predicts platinum sensitivity in ovarian cancer
topic Genome and Epigenome
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338879/
https://www.ncbi.nlm.nih.gov/pubmed/34224372
http://dx.doi.org/10.1158/0008-5472.CAN-21-0953
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