Abstract
MicroRNAs (miRNAs) are small RNA molecules that modulate gene expression implicated in cancer, which play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. The aim of this study was to investigate whether miR-30c mediated the resistance of breast cancer cells to the chemotherapeutic agent doxorubicin (ADR) by targeting tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ). miR-30c was downregulated in the doxorubicin-resistant human breast cancer cell lines MCF-7/ADR and MDA-MB-231/ADR compared with their parental MCF-7 and MDA-MB-231 cell lines, respectively. Furthermore, we observed that transfection of an miR-30c mimic significantly suppressed the ability of MCF-7/ADR to resist doxorubicin. Moreover, the anti-apoptotic gene YWHAZ was confirmed as a target of miR-30c by luciferase reporter assay, and further studies indicated that the mechanism for miR-30c on the sensitivity of breast cancer cells involved YWHAZ and its downstream p38 mitogen-activated protein kinase (p38MAPK) pathway. Together, our findings provided evidence that miR-30c was one of the important miRNAs in doxorubicin resistance by regulating YWHAZ in the breast cancer cell line MCF-7/ADR.
Highlights
Breast cancer is the most commonly diagnosed cancer worldwide among women and is expected to account for 29% of all new cancer cases [1]
The aim of this study was to investigate whether miR-30c mediated the resistance of breast cancer cells to the chemotherapeutic agent doxorubicin (ADR) by targeting tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ). miR-30c was downregulated in the doxorubicin-resistant human breast cancer cell lines MCF-7/ADR and MDA-MB-231/ADR compared with their parental MCF-7 and MDA-MB-231 cell lines, respectively
The anti-apoptotic gene YWHAZ was confirmed as a target of miR-30c by luciferase reporter assay, and further studies indicated that the mechanism for miR-30c on the sensitivity of breast cancer cells involved YWHAZ and its downstream p38 mitogen-activated protein kinase (p38MAPK) pathway
Summary
Breast cancer is the most commonly diagnosed cancer worldwide among women and is expected to account for 29% of all new cancer cases [1]. Chemotherapeutic failure frequently contributes to morbidity in patients diagnosed with breast cancer [2], and the acquisition of resistance to doxorubicin is a major clinical obstacle to successful treatment. It is essential to elucidate the signaling and regulatory mechanisms that are involved in doxorubicin resistance, which will be helpful for designing new and targeted therapeutic strategies that can overcome drug resistance for the treatment of breast cancer. Some studies suggested that miRNAs are involved in tumor cell resistance and/or sensitivity to chemotherapeutic agents [4]. Zhu et al [5] reported that both miR-451 and miR-27 are involved in the resistance of MCF-7 breast cancer cells to the chemotherapeutic drug doxorubicin mediated by MDR-1 [5,6]
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