MiR-455-DNMT3A signaling is linked toacquisition of doxorubicinresistance in breast cancer
نویسندگان
چکیده
Breast cancer cells can develop resistance to chemotherapeutic agents. Epigenetic changes such as DNA methylation and histone modifications have been shown to play a critical role in acquisition of drug resistance bythese cells. microRNAs (miRNAs) are a class of short non-coding RNAs that are closely associated with cancer chemoresistance through regulating the genes involved in epigenetic modifications. In this study, we used a variety of biochemical techniques including cell culture, RT-PCR, Western blot, luciferase reporter assay, MTT and gene silencing to investigate the role of miR-455 in the resistance of human MCF-7 breast adenocarcinoma cells to doxorubicin (DOX). We demonstrated that DOX-resistant MCF-7 cells (MCF-7/DOX) show significant up-regulation of miR-455 compared to normal MCF-7 cells. The mechanistic link between miR-455 deregulation and DOXresistant phenotype in MCF-7/DOX ismediated by DNMT3A. Specifically, we showed that microRNA-455 down-regulates the expression of DNMT3A, thus possibly leading to global loss of DNA methylation in MCF-7/DOX cells. Furthermore, transfection of the MCF-7 cells with siRNAs targeting degradation of DNMT3 reduced their sensitivity to DOX. Our results support the idea that manipulating expression of miRNAs may have significant implications for therapeutic strategies aimedat overcoming thebreast cancer resistance.
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تاریخ انتشار 2017