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MiR-140 leads to MRE11 downregulation and ameliorates oxaliplatin treatment and therapy response in colorectal cancer patients
Cancer therapy failure is a fundamental challenge in cancer treatment. One of the most common reasons for therapy failure is the development of acquired resistance of cancer cells. DNA-damaging agents are frequently used in first-line chemotherapy regimens and DNA damage response, and DNA repair pat...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618941/ https://www.ncbi.nlm.nih.gov/pubmed/36324569 http://dx.doi.org/10.3389/fonc.2022.959407 |
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author | Horak, Josef Dolnikova, Alexandra Cumaogullari, Ozge Cumova, Andrea Navvabi, Nazila Vodickova, Ludmila Levy, Miroslav Schneiderova, Michaela Liska, Vaclav Andera, Ladislav Vodicka, Pavel Opattova, Alena |
author_facet | Horak, Josef Dolnikova, Alexandra Cumaogullari, Ozge Cumova, Andrea Navvabi, Nazila Vodickova, Ludmila Levy, Miroslav Schneiderova, Michaela Liska, Vaclav Andera, Ladislav Vodicka, Pavel Opattova, Alena |
author_sort | Horak, Josef |
collection | PubMed |
description | Cancer therapy failure is a fundamental challenge in cancer treatment. One of the most common reasons for therapy failure is the development of acquired resistance of cancer cells. DNA-damaging agents are frequently used in first-line chemotherapy regimens and DNA damage response, and DNA repair pathways are significantly involved in the mechanisms of chemoresistance. MRE11, a part of the MRN complex involved in double-strand break (DSB) repair, is connected to colorectal cancer (CRC) patients’ prognosis. Our previous results showed that single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′UTR) microRNA (miRNA) binding sites of MRE11 gene are associated with decreased cancer risk but with shorter survival of CRC patients, which implies the role of miRNA regulation in CRC. The therapy of colorectal cancer utilizes oxaliplatin (oxalato(trans-l-1,2-diaminocyclohexane)platinum), which is often compromised by chemoresistance development. There is, therefore, a crucial clinical need to understand the cellular processes associated with drug resistance and improve treatment responses by applying efficient combination therapies. The main aim of this study was to investigate the effect of miRNAs on the oxaliplatin therapy response of CRC patients. By the in silico analysis, miR-140 was predicted to target MRE11 and modulate CRC prognosis. The lower expression of miR-140 was associated with the metastatic phenotype (p < 0.05) and poor progression-free survival (odds ratio (OR) = 0.4, p < 0.05). In the in vitro analysis, we used miRNA mimics to increase the level of miR-140 in the CRC cell line. This resulted in decreased proliferation of CRC cells (p < 0.05). Increased levels of miR-140 also led to increased sensitivity of cancer cells to oxaliplatin (p < 0.05) and to the accumulation of DNA damage. Our results, both in vitro and in vivo, suggest that miR-140 may act as a tumor suppressor and plays an important role in DSB DNA repair and, consequently, CRC therapy response. |
format | Online Article Text |
id | pubmed-9618941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96189412022-11-01 MiR-140 leads to MRE11 downregulation and ameliorates oxaliplatin treatment and therapy response in colorectal cancer patients Horak, Josef Dolnikova, Alexandra Cumaogullari, Ozge Cumova, Andrea Navvabi, Nazila Vodickova, Ludmila Levy, Miroslav Schneiderova, Michaela Liska, Vaclav Andera, Ladislav Vodicka, Pavel Opattova, Alena Front Oncol Oncology Cancer therapy failure is a fundamental challenge in cancer treatment. One of the most common reasons for therapy failure is the development of acquired resistance of cancer cells. DNA-damaging agents are frequently used in first-line chemotherapy regimens and DNA damage response, and DNA repair pathways are significantly involved in the mechanisms of chemoresistance. MRE11, a part of the MRN complex involved in double-strand break (DSB) repair, is connected to colorectal cancer (CRC) patients’ prognosis. Our previous results showed that single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′UTR) microRNA (miRNA) binding sites of MRE11 gene are associated with decreased cancer risk but with shorter survival of CRC patients, which implies the role of miRNA regulation in CRC. The therapy of colorectal cancer utilizes oxaliplatin (oxalato(trans-l-1,2-diaminocyclohexane)platinum), which is often compromised by chemoresistance development. There is, therefore, a crucial clinical need to understand the cellular processes associated with drug resistance and improve treatment responses by applying efficient combination therapies. The main aim of this study was to investigate the effect of miRNAs on the oxaliplatin therapy response of CRC patients. By the in silico analysis, miR-140 was predicted to target MRE11 and modulate CRC prognosis. The lower expression of miR-140 was associated with the metastatic phenotype (p < 0.05) and poor progression-free survival (odds ratio (OR) = 0.4, p < 0.05). In the in vitro analysis, we used miRNA mimics to increase the level of miR-140 in the CRC cell line. This resulted in decreased proliferation of CRC cells (p < 0.05). Increased levels of miR-140 also led to increased sensitivity of cancer cells to oxaliplatin (p < 0.05) and to the accumulation of DNA damage. Our results, both in vitro and in vivo, suggest that miR-140 may act as a tumor suppressor and plays an important role in DSB DNA repair and, consequently, CRC therapy response. Frontiers Media S.A. 2022-10-17 /pmc/articles/PMC9618941/ /pubmed/36324569 http://dx.doi.org/10.3389/fonc.2022.959407 Text en Copyright © 2022 Horak, Dolnikova, Cumaogullari, Cumova, Navvabi, Vodickova, Levy, Schneiderova, Liska, Andera, Vodicka and Opattova https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Horak, Josef Dolnikova, Alexandra Cumaogullari, Ozge Cumova, Andrea Navvabi, Nazila Vodickova, Ludmila Levy, Miroslav Schneiderova, Michaela Liska, Vaclav Andera, Ladislav Vodicka, Pavel Opattova, Alena MiR-140 leads to MRE11 downregulation and ameliorates oxaliplatin treatment and therapy response in colorectal cancer patients |
title | MiR-140 leads to MRE11 downregulation and ameliorates oxaliplatin treatment and therapy response in colorectal cancer patients |
title_full | MiR-140 leads to MRE11 downregulation and ameliorates oxaliplatin treatment and therapy response in colorectal cancer patients |
title_fullStr | MiR-140 leads to MRE11 downregulation and ameliorates oxaliplatin treatment and therapy response in colorectal cancer patients |
title_full_unstemmed | MiR-140 leads to MRE11 downregulation and ameliorates oxaliplatin treatment and therapy response in colorectal cancer patients |
title_short | MiR-140 leads to MRE11 downregulation and ameliorates oxaliplatin treatment and therapy response in colorectal cancer patients |
title_sort | mir-140 leads to mre11 downregulation and ameliorates oxaliplatin treatment and therapy response in colorectal cancer patients |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618941/ https://www.ncbi.nlm.nih.gov/pubmed/36324569 http://dx.doi.org/10.3389/fonc.2022.959407 |
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