MicroRNA-33a-5p overexpression sensitizes triple-negative breast cancer to doxorubicin by inhibiting eIF5A2 and epithelial-mesenchymal transition.

Abstract

Drug resistance is a significant obstacle when treating triple-negative breast cancer (TNBC). Several studies have demonstrated that microRNAs (miRNAs) have essential roles in regulating drug resistance in different types of cancer. miR-33a-5p has previously been reported to be a tumor suppressor in several types of cancer. However, its role in breast cancer remains unknown. The present study aimed to investigate the role of miR-33a-5p in the chemoresistance of TNBC and uncover its potential molecular mechanisms. Cell Counting Kit-8 assay was used to examine cell proliferation, reverse transcription-quantitative PCR analysis was used to examine miR-33a levels, and western blotting and immunofluorescence assays were used to examine the expression of epithelial-mesenchymal transition (EMT)-associated proteins and of eukaryotic translation initiation factor 5A2 (eIF5A2). The results indicated that miR-33a-5p expression was lower in TNBC cells compared with non-TNBC cells. miR-33a-5p overexpression significantly improved the doxorubicin (Dox) sensitivity of TNBC cells, but not that of non-TNBC cells. It was then observed that Dox treatment inhibited miR-33a-5p expression and induced EMT in TNBC cells, by increasing the expression levels of vimentin, while decreasing the expression levels of E-cadherin. Furthermore, it was revealed that forced expression of miR-33a-5p attenuated Dox-induced EMT. eIF5A2 was identified as a potential target of miR-33a-5p, and miR-33a-5p overexpression inhibited the expression of eIF5A2. eIF5A2 inhibition, via its inhibitor GC7, sensitized TNBC cells to Dox and reversed Dox-induced EMT. Overall, the present study demonstrated that miR-33a-5p enhanced the sensitivity of TNBC cells to Dox, by suppressing eIF5A2 expression and reversing Dox-induced EMT, providing a potential therapeutic target for treating drug-resistant TNBC.