MicroRNA-29a enhances cisplatin sensitivity in non-small cell lung cancer through the regulation of REV3L

Cisplatin-based chemotherapy may greatly enhance patient prognosis; however, chemotherapy resistance remains an obstacle to curing patients with non-small cell lung cancer (NSCLC). The aim of the present study was to explore the microRNAs (miRs) that could regulate cisplatin sensitivity and provide a potential treatment method for cisplatin resistance in clinical. Results from the present study revealed that miR-29a overexpression enhanced and miR-29a inhibition reduced the sensitivity of two NSCLC cell lines, A549 and H1650, to cisplatin treatment. In addition, reduced miR-29a expression levels were observed in cisplatin-resistant A549 cells (A549rCDDP), and increased expression of miR-29a augmented cisplatin-induced inhibition of proliferation and apoptosis in A549rCDDP cells. These data indicated that miR-29a expression may be involved in the development of cisplatin resistance. miR-29a was revealed to negatively regulate REV3-like DNA-directed polymerase catalytic subunit (REV3L) expression in both A549 and H1650 cells; elevated expression of REV3L in A549rCDDP cells was also detected. REV3L encodes the catalytic subunit of DNA polymerase and was hypothesized, based on results from the online tool TargetScan 7.1, to be a target gene of miR-29a; this was confirmed with a dual luciferase assay. Cells treated with a very low concentration of cisplatin exhibited a significant reduction in proliferation and cell cycle arrest at the G2/M phase in REV3L-knockdown as well as in miR-29a-upregulated A549 cells. Notably, reduced miR-29a expression and an increase in REV3L mRNA expression were observed in tumor tissues from patients with NSCLC. Additionally, a negative correlation between miR-29a and REV3L mRNA expression levels in tumor tissues from patients with NSCLC was observed; low expression of miR-29a and high expression of REV3L were closely associated with an advanced tumor-node-metastasis classification. The results of the present study suggested a pivotal role of miR-29a in mediating NSCLC cell sensitivity towards cisplatin through the regulation of REV3L.