Cisplatin resistance presents a major challenge in the successful treatment of breast cancer, and its mechanism has not been documented well. In this study, to determine the relationship between chemotherapy resistance and microRNA (miRNA) expression during the development of cisplatin resistance in breast cancer, we used microRNA microarrays analysis successfully identified 19 miRNAs that were either overexpressed or underexpressed (8 upregulated and 11 downregulated) in the MCF-7 cell line and its cisplatin-resistant variant MCF-7/DDP. Among them, the miR-218 was most downregulated in cisplatin-resistant cell lines and identified that breast cancer 1 (BRCA1) was the cellular targets of miR-218. In vivo assay also demonstrated that restoring miR-218 expression in MCF-7/DDP cell line could sensitize cells against cisplatin, thereby increasing cisplatin-mediated tumor cell apoptosis and reducing DNA repair. Kaplan-Meier survival analysis indicated that patients with breast cancer display high levels of miR-218 and low levels of BRCA1 expression; these patients may gain the greatest benefits in terms of increased survival when treated with cisplatin. All of these results indicated that miR-218 has a significant function in the development of cisplatin resistance in breast cancer. Restoring miR-218 expression may constitute a novel therapeutic approach by which to increase cisplatin sensitivity in breast cancer.
The administration of doxorubicin (DOX) is one of the first‐line treatments of breast cancer. However, acquisition of resistance remains the major obstacle restricting the clinical application of DOX. MicroRNAs (miRNAs) are small, noncoding RNAs which play crucial role in epigenetic regulation. Recent studies have shown that miRNAs are associated with tumor chemoresistance. Here we aim to explore the role of miRNA‐192‐5p in resistance to DOX in breast cancer cells. Normal human breast epithelial cell line MCF‐10A, breast cancer cell line Michigan Cancer Foundation‐7 (MCF‐7), and DOX‐resistant breast cancer cell line MCF‐7/ADR were used here. The expression of miR‐192‐5p was examined by qPCR, and the expression of peptidylprolyl isomerase A (PPIA) was examined by qPCR and Western blot. The effects of miR‐192‐5p overexpression on the sensitivity to DOX were confirmed by Methylthiazolyldiphenyl‐tetrazolium bromide (MTT) and Annexin‐V/PI assay. Downstream molecular mechanisms, including PPIA, BAD, CASP9, Bcl‐2, and c‐Jun N‐terminal kinase (JNK) activation, were detected by Western blot and qPCR. Luciferase reporter assay was used to validate the association between miR‐192‐5p and PPIA. miR‐192‐5p was downregulated while PPIA was upregulated in MCF‐7/ADR cells. Functionally, miR‐192‐5p overexpression increased sensitivity to DOX by promoting cell apoptosis. Mechanistically, miR‐192‐5p overexpression performed its function by activating JNK, augmenting BAD and caspase9 expression, and suppressing Bcl‐2 and PPIA expression. Luciferase assay validated that PPIA was a direct target of miR‐192‐5p. miR‐192‐5p sensitizes breast cancer cells to DOX by targeting PPIA, suggesting that miR‐192‐5p might serve as a novel target for reversing DOX resistance and controlling breast tumor growth.
In patients undergoing a mastectomy, postoperative analgesia with flurbiprofen axetil, combined with fentanyl, were associated with decreases in serum concentrations of VEGF-C, TNF-α, and IL-1ß compared with patients receiving doses of only fentanyl.
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