MiR-221-3p-mediated downregulation of MDM2 reverses the paclitaxel resistance of non-small cell lung cancer in vitro and in vivo

• Published in: European journal of pharmacology 2021-05, Vol.899, p.174054-174054, Article 174054
• Main Authors: Ni, Liwei, Xu, Jianhao, Zhao, Fenglun, Dai, Xiaoxiao, Tao, Jialong, Pan, Jie, Shi, Aiming, Shen, Zhu, Su, Cunjin, Zhang, Yusong
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Down-Regulation; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; MDM2; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; miR-221–3p; Non-small cell lung cancer; P53; Paclitaxel - pharmacology; Paclitaxel resistance; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Signal Transduction; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174054

MicroRNAs (miRNAs) are involved in the initiation and development of cancer and participate in drug resistance. Paclitaxel (PTX) is a first-line chemotherapy drug for advanced non-small cell lung cancer (NSCLC). The abnormal miRNA expression in NSCLC and its association with chemotherapy drug resistance remains largely unknown. The study aimed to investigate the aberrant expression of miR-221–3p in NSCLC and to elucidate its molecular mechanisms in relation to PTX resistance. PTX increased miR-221–3p expression and regulated MDM2/P53 expression in the PTX-sensitive NSCLC strain (A549). Meanwhile, miR-221–3p was rarely expressed and not interfered by PTX in PTX-resistant A549 cells (A549/Taxol). Dual-luciferase reporter assay confirmed that miR-221–3p specifically binds to MDM2 messenger RNA and inhibited MDM2 expression. The expression of MDM2 and P53 showed a negative correlation in NSCLC cell lines. MiR-221–3p down-regulation reduced the sensitivity of A549 cells to PTX, whereas its up-regulation partially reversed the A549/Taxol cells resistance to PTX and increased the chemosensitivity of A549/Taxol cells to PTX in xenograft models. Quantitative polymerase chain reaction analysis revealed that miR-221–3p expression increased, whereas the MDM2 level decreased in human NSCLC tumor tissues. Moreover, Western bolt analysis showed that P53 was lowly expressed in tumor tissues with MDM2 overexpression. Low expression of miR-221–3p in NSCLC tissues might indicate a poor T staging. In conclusion, miR-221–3p overexpression could regulate MDM2/p53 signaling pathway to reverse the PTX resistance of NSCLC and induce apoptosis in vitro and vivo. •Chemotherapy resistance is a major impediment to treatment of lung cancer (LC).•Aberrant expression of miRNAs in LC is associated with chemotherapy resistance.•MiR-221–3p overexpression reverses the paclitaxel resistance of LC via MDM2/p53 axis.•Exploring the chemoresistance mechanisms promotes the development of antitumor drugs.