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DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells
One of the major limitations associated with platinum use is the resistance that almost invariably develops in different tumor types. In the current study, we sought to identify epigenetically regulated microRNAs as novel biomarkers of platinum resistance in lung and ovarian cancers, the ones with h...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695001/ https://www.ncbi.nlm.nih.gov/pubmed/29158814 http://dx.doi.org/10.7150/thno.20112 |
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author | Vera, Olga Jimenez, Julia Pernia, Olga Rodriguez-Antolin, Carlos Rodriguez, Carmen Sanchez Cabo, Fatima Soto, Javier Rosas, Rocio Lopez-Magallon, Sara Esteban Rodriguez, Isabel Dopazo, Ana Rojo, Federico Belda, Cristobal Alvarez, Rafael Valentin, Jaime Benitez, Javier Perona, Rosario De Castro, Javier Ibanez de Caceres, Inmaculada |
author_facet | Vera, Olga Jimenez, Julia Pernia, Olga Rodriguez-Antolin, Carlos Rodriguez, Carmen Sanchez Cabo, Fatima Soto, Javier Rosas, Rocio Lopez-Magallon, Sara Esteban Rodriguez, Isabel Dopazo, Ana Rojo, Federico Belda, Cristobal Alvarez, Rafael Valentin, Jaime Benitez, Javier Perona, Rosario De Castro, Javier Ibanez de Caceres, Inmaculada |
author_sort | Vera, Olga |
collection | PubMed |
description | One of the major limitations associated with platinum use is the resistance that almost invariably develops in different tumor types. In the current study, we sought to identify epigenetically regulated microRNAs as novel biomarkers of platinum resistance in lung and ovarian cancers, the ones with highest ratios of associated chemo-resistance. Methods: We combined transcriptomic data from microRNA and mRNA under the influence of an epigenetic reactivation treatment in a panel of four paired cisplatin -sensitive and -resistant cell lines, followed by real-time expression and epigenetic validations for accurate candidate selection in 19 human cancer cell lines. To identify specific candidate genes under miRNA regulation, we assembled “in silico” miRNAs and mRNAs sequences by using ten different algorithms followed by qRT-PCR validation. Functional assays of site-directed mutagenesis and luciferase activity, miRNAs precursor overexpression, silencing by antago-miR and cell viability were performed to confirm their specificity in gene regulation. Results were further explored in 187 primary samples obtained from ovarian tumors and controls. Results: We identified 4 candidates, miR-7, miR-132, miR-335 and miR-148a, which deregulation seems to be a common event in the development of resistance to cisplatin in both tumor types. miR-7 presented specific methylation in resistant cell lines, and was associated with poorer prognosis in ovarian cancer patients. Our experimental results strongly support the direct regulation of MAFG through miR-7 and their involvement in the development of CDDP resistance in human tumor cells. Conclusion: The basal methylation status of miR-7 before treatment may be a potential clinical epigenetic biomarker, predictor of the chemotherapy outcome to CDDP in ovarian cancer patients. To the best of our knowledge, this is the first report linking the regulation of MAFG by miRNA-7 and its role in chemotherapy response to CDDP. Furthermore, this data highlights the possible role of MAFG as a novel therapeutic target for platinum resistant tumors. |
format | Online Article Text |
id | pubmed-5695001 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-56950012017-11-20 DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells Vera, Olga Jimenez, Julia Pernia, Olga Rodriguez-Antolin, Carlos Rodriguez, Carmen Sanchez Cabo, Fatima Soto, Javier Rosas, Rocio Lopez-Magallon, Sara Esteban Rodriguez, Isabel Dopazo, Ana Rojo, Federico Belda, Cristobal Alvarez, Rafael Valentin, Jaime Benitez, Javier Perona, Rosario De Castro, Javier Ibanez de Caceres, Inmaculada Theranostics Research Paper One of the major limitations associated with platinum use is the resistance that almost invariably develops in different tumor types. In the current study, we sought to identify epigenetically regulated microRNAs as novel biomarkers of platinum resistance in lung and ovarian cancers, the ones with highest ratios of associated chemo-resistance. Methods: We combined transcriptomic data from microRNA and mRNA under the influence of an epigenetic reactivation treatment in a panel of four paired cisplatin -sensitive and -resistant cell lines, followed by real-time expression and epigenetic validations for accurate candidate selection in 19 human cancer cell lines. To identify specific candidate genes under miRNA regulation, we assembled “in silico” miRNAs and mRNAs sequences by using ten different algorithms followed by qRT-PCR validation. Functional assays of site-directed mutagenesis and luciferase activity, miRNAs precursor overexpression, silencing by antago-miR and cell viability were performed to confirm their specificity in gene regulation. Results were further explored in 187 primary samples obtained from ovarian tumors and controls. Results: We identified 4 candidates, miR-7, miR-132, miR-335 and miR-148a, which deregulation seems to be a common event in the development of resistance to cisplatin in both tumor types. miR-7 presented specific methylation in resistant cell lines, and was associated with poorer prognosis in ovarian cancer patients. Our experimental results strongly support the direct regulation of MAFG through miR-7 and their involvement in the development of CDDP resistance in human tumor cells. Conclusion: The basal methylation status of miR-7 before treatment may be a potential clinical epigenetic biomarker, predictor of the chemotherapy outcome to CDDP in ovarian cancer patients. To the best of our knowledge, this is the first report linking the regulation of MAFG by miRNA-7 and its role in chemotherapy response to CDDP. Furthermore, this data highlights the possible role of MAFG as a novel therapeutic target for platinum resistant tumors. Ivyspring International Publisher 2017-09-22 /pmc/articles/PMC5695001/ /pubmed/29158814 http://dx.doi.org/10.7150/thno.20112 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Vera, Olga Jimenez, Julia Pernia, Olga Rodriguez-Antolin, Carlos Rodriguez, Carmen Sanchez Cabo, Fatima Soto, Javier Rosas, Rocio Lopez-Magallon, Sara Esteban Rodriguez, Isabel Dopazo, Ana Rojo, Federico Belda, Cristobal Alvarez, Rafael Valentin, Jaime Benitez, Javier Perona, Rosario De Castro, Javier Ibanez de Caceres, Inmaculada DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells |
title | DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells |
title_full | DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells |
title_fullStr | DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells |
title_full_unstemmed | DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells |
title_short | DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells |
title_sort | dna methylation of mir-7 is a mechanism involved in platinum response through mafg overexpression in cancer cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695001/ https://www.ncbi.nlm.nih.gov/pubmed/29158814 http://dx.doi.org/10.7150/thno.20112 |
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