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Screening of acetaminophen-induced alterations in epithelial-to-mesenchymal transition-related expression of microRNAs in a model of stem-like triple-negative breast cancer cells: The possible functional impacts

Afshar, Elham, Hashemi-Arabi, Masoud, Salami, Siamak, Peirouvi, Tahmineh, Pouriran, Ramin
Gene 2019 v.702 pp. 46-55
acetaminophen, breast neoplasms, cadherins, epithelium, gene expression regulation, genes, microRNA, models, neoplasm cells, phenotype, pleiotropy, screening, stem cells, therapeutics, vimentin
Current protocols for therapy inefficiently targets triple negative breast cancer and barely eradicate cancer stem cells. Elucidation of the pleiotropic effect of clinically proven therapeutics on cancer cells shed light on novel application of old friends. The pleiotropic effect of acetaminophen (APAP) on breast cancer was previously reported. In a cell model of triple negative breast cancer with stem-like CD44high/CD24low phenotype, we screened the impacts of APAP (1 mM, 72 h) on the Epithelial to mesenchymal transition (EMT)-related expression of miRs. APAP significantly overexpressed hsa-miR-130a-3p, 192-5p, 214-3p, 101-3p, 30d-5p, 10a-5p, 99a-5p, 200c-3p, 143-3p, 30b-5p and let-7f-5p showed significant overexpression, but suppressed the expression of hsa-miR-7-5p, 149-3p, 215, 150-5p, 205-5p, 206, 10b-5p, 20b-5p, 145-5p, 26b-5p, 223-3p, 17-5p, 186-5p, 146a-5p and let-7c. It also altered on the expression of selected EMT-related genes, significantly upregulated the expression of KRT19, AKT2, CD24, and TIMP1; but downregulated the expression of MMP2, ALDH1, MMP9, TWIST, NOTCH1, and AKT1. Such shifts in expression profiles increased the population of the cells with CD44high/CD24high, and CD44low/CD24high phenotypes, significantly reduced the Twist protein and shifted the balance of E-cadherin and Vimentin proteins in favor of differentiation. Treated cells showed a significant reduction of in vitro migration and were significantly chemosensitized to Camptothecin. In conclusion, APAP, at a safe clinical dose, induced a set of targeted alterations in the EMT-related miRs which implicate, even in part, significant mitigation in chemoresistance and in vitro migration. Further studies should also be piloted to elucidate the most crucial miRs and to evaluate its clinical effectiveness.