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 ζ 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 ζ 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.