MicroRNA-10b modulates cisplatin tolerance by targeting p53 directly in lung cancer cells

MicroRNA (miRNA or miR)-10b is an oncogenic miRNA associated with metastasis that is present in various types of tumor, including lung cancer. However, whether miR-10b is involved in different malignant characteristics, such as drug resistance or stemness, remains unclear. Therefore, the present study investigated whether miR-10b is an upstream regulator of p53. Ectopic expression of miR-10b-agomir decreased the expression of p53 and its downstream effectors, such as Bax and p53 upregulated modulator of apoptosis. Two non-canonical sites, including 1,580-1,587 and 2,029-2,035, located in p53 3 '-untranslated region (UTR) were affected by the presence of miR-10b. In functional assays, upregulation of the p53 signaling pathway following cisplatin treatment was associated with decreased levels of miR-10b and upregulation of the luciferase activity of wild-type, but not 1,584, 2,032-dual-mutant, p53 3 '-UTR. The ectopic expression of miR-10b-agomir attenuated the stability of p53 3 '-UTR and the expression of p53 and its downstream effectors induced by cisplatin. By contrast, the knockdown of miR-10b induced the stability of p53 3 '-UTR and increased levels of p53 and the sensitivity of A549 cells to cisplatin treatment. Similar results were also observed for Beas 2B cells. In the clinical investigation, p53 exhibited two distinct associations (cocurrent and countercurrent) with miR-10b in patients with lung cancer. Patients with lung cancer with low p53 and high miR-10b levels exhibited the poorest prognosis, while those with high p53 and low miR-10b exhibited the most favorable prognosis. These findings indicate a novel pathway in which cisplatin induces the levels of p53 by increasing mRNA stability via miR-10b, indicating a novel oncogenic role of miR-10b in promoting the malignant characteristics of non-small cell lung carcinoma.