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Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage
FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers o...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602334/ https://www.ncbi.nlm.nih.gov/pubmed/34795259 http://dx.doi.org/10.1038/s41467-021-27099-6 |
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author | Carotenuto, Pietro Amato, Francesco Lampis, Andrea Rae, Colin Hedayat, Somaieh Previdi, Maria C. Zito, Domenico Raj, Maya Guzzardo, Vincenza Sclafani, Francesco Lanese, Andrea Parisi, Claudia Vicentini, Caterina Said-Huntingford, Ian Hahne, Jens C. Hallsworth, Albert Kirkin, Vladimir Young, Kate Begum, Ruwaida Wotherspoon, Andrew Kouvelakis, Kyriakos Azevedo, Sergio Xavier Michalarea, Vasiliki Upstill-Goddard, Rosie Rao, Sheela Watkins, David Starling, Naureen Sadanandam, Anguraj Chang, David K. Biankin, Andrew V. Jamieson, Nigel B. Scarpa, Aldo Cunningham, David Chau, Ian Workman, Paul Fassan, Matteo Valeri, Nicola Braconi, Chiara |
author_facet | Carotenuto, Pietro Amato, Francesco Lampis, Andrea Rae, Colin Hedayat, Somaieh Previdi, Maria C. Zito, Domenico Raj, Maya Guzzardo, Vincenza Sclafani, Francesco Lanese, Andrea Parisi, Claudia Vicentini, Caterina Said-Huntingford, Ian Hahne, Jens C. Hallsworth, Albert Kirkin, Vladimir Young, Kate Begum, Ruwaida Wotherspoon, Andrew Kouvelakis, Kyriakos Azevedo, Sergio Xavier Michalarea, Vasiliki Upstill-Goddard, Rosie Rao, Sheela Watkins, David Starling, Naureen Sadanandam, Anguraj Chang, David K. Biankin, Andrew V. Jamieson, Nigel B. Scarpa, Aldo Cunningham, David Chau, Ian Workman, Paul Fassan, Matteo Valeri, Nicola Braconi, Chiara |
author_sort | Carotenuto, Pietro |
collection | PubMed |
description | FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome. |
format | Online Article Text |
id | pubmed-8602334 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86023342021-11-19 Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage Carotenuto, Pietro Amato, Francesco Lampis, Andrea Rae, Colin Hedayat, Somaieh Previdi, Maria C. Zito, Domenico Raj, Maya Guzzardo, Vincenza Sclafani, Francesco Lanese, Andrea Parisi, Claudia Vicentini, Caterina Said-Huntingford, Ian Hahne, Jens C. Hallsworth, Albert Kirkin, Vladimir Young, Kate Begum, Ruwaida Wotherspoon, Andrew Kouvelakis, Kyriakos Azevedo, Sergio Xavier Michalarea, Vasiliki Upstill-Goddard, Rosie Rao, Sheela Watkins, David Starling, Naureen Sadanandam, Anguraj Chang, David K. Biankin, Andrew V. Jamieson, Nigel B. Scarpa, Aldo Cunningham, David Chau, Ian Workman, Paul Fassan, Matteo Valeri, Nicola Braconi, Chiara Nat Commun Article FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome. Nature Publishing Group UK 2021-11-18 /pmc/articles/PMC8602334/ /pubmed/34795259 http://dx.doi.org/10.1038/s41467-021-27099-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Carotenuto, Pietro Amato, Francesco Lampis, Andrea Rae, Colin Hedayat, Somaieh Previdi, Maria C. Zito, Domenico Raj, Maya Guzzardo, Vincenza Sclafani, Francesco Lanese, Andrea Parisi, Claudia Vicentini, Caterina Said-Huntingford, Ian Hahne, Jens C. Hallsworth, Albert Kirkin, Vladimir Young, Kate Begum, Ruwaida Wotherspoon, Andrew Kouvelakis, Kyriakos Azevedo, Sergio Xavier Michalarea, Vasiliki Upstill-Goddard, Rosie Rao, Sheela Watkins, David Starling, Naureen Sadanandam, Anguraj Chang, David K. Biankin, Andrew V. Jamieson, Nigel B. Scarpa, Aldo Cunningham, David Chau, Ian Workman, Paul Fassan, Matteo Valeri, Nicola Braconi, Chiara Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage |
title | Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage |
title_full | Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage |
title_fullStr | Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage |
title_full_unstemmed | Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage |
title_short | Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage |
title_sort | modulation of pancreatic cancer cell sensitivity to folfirinox through microrna-mediated regulation of dna damage |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602334/ https://www.ncbi.nlm.nih.gov/pubmed/34795259 http://dx.doi.org/10.1038/s41467-021-27099-6 |
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