2024-03-28T18:51:25Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/71542023-09-28T13:17:08Zcom_20.500.12105_2174com_20.500.12105_2051com_20.500.12105_2173com_20.500.12105_2152com_20.500.12105_2144col_20.500.12105_2175col_20.500.12105_2153
00925njm 22002777a 4500
dc
Vera, Olga
author
Jimenez, Julia
author
Pernia, Olga
author
Rodriguez-Antolin, Carlos
author
Rodriguez, Carmen
author
Sanchez-Cabo, Fatima
author
Soto, Javier
author
Rosas, RocĂo
author
Lopez-Magallon, Sara
author
Esteban Rodriguez, Isabel
author
Dopazo, Ana
author
Rojo, Federico
author
Belda-Iniesta, Cristobal
author
Alvarez, Rafael
author
Valentin, Jaime
author
Benitez, Javier
author
Perona, Rosario
author
De Castro, Javier
author
Ibanez de Caceres, Inmaculada
author
2017
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.
Theranostics. 2017; 7(17):4118-4134
1838-7640
http://hdl.handle.net/20.500.12105/7154
29158814
10.7150/thno.20112
1838-7640
Theranostics
Cisplatin-resistance
DNA methylation
MAFG
Cancer
miR-7
DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells