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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2017
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.
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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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