miRNA‐192‐5p impacts the sensitivity of breast cancer cells to doxorubicin via targeting peptidylprolyl isomerase A

Abstract

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.

Chemotherapeutic Stress Influences Epithelial–Mesenchymal Transition and Stemness in Cancer Stem Cells of Triple-Negative Breast Cancer

“…MiR-375 was reported to inhibit EMT in breast cancer while inducing docetaxel resistance in prostate cancer [47,50]. MiR-192-5p was significantly abolished in hepatocellular carcinomas expressing high levels of CSC markers, but enhanced doxorubicin sensitivity in breast cancer [51,52]. MiR-21-3p played an important role in mediating cisplatin resistance in ovarian cancer and reduced TRAIL-mediated apoptosis in liver cancer stem cell [34,35].…”

miR-192-5p suppresses the progression of lung cancer bone metastasis by targeting TRIM44

“…Ectopic expression of miR-192 may be related to tumour occurrence as it exerts a significant effect on the progression of various malignancies. Recent studies have reported that miR-192 is considerably reduced in many malignant tumours and may be involved in regulating the proliferation, migration, and invasion of cancer cells in neoplasms 20,21,30,31 . For instance, Ji et al 30 suggested that miR-192-5p was significantly reduced in human bladder cancer.…”

“…In addition, many studies have already demonstrated that miRNA dysfunction is involved in the occurrence and progression of malignancies, such as breast cancer, gastric carcinoma, prostate cancer, and lung cancer [16][17][18][19] . In recent years, various studies have shown that miR-192-5p is significantly downregulated in malignant carcinoma, while miR-192-5p overexpression may play a potential role in suppressing tumourigenesis through different mechanisms 20,21 . In lung cancer bone metastasis, miR-192-5p plays a major role in inhibiting tumourigenesis 22,23 .…”

Role of non-coding RNAs and RNA modifiers in cancer therapy resistance

“…DOX is another chemotherapy used clinically. Significantly high level of miR-216a, miR-124-3p, miR-148/152, miR-192-5p, miR-181c, miR-381, and miR-489 have been documented to be linked with DOX sensitivity in BC cell lines [85,86,[136][137][138][139][140]. Among them, miR-181c modulates drug efficiency through inactivating its downstream gene OPN (osteopontin), leading to enhanced p53-dependent transactivation and apoptosis in resistant BC cells [85].…”