Abstract
Radioresistance is a major problem encountered in the treatment of non-small cell lung cancer (NSCLC). Aberrant microRNA (miRNA) expression contributes to multiple cancer-associated signaling pathways and profoundly influences effects of radiotherapy (RT) in cancers. MicroRNA-145-5p (miR-145) is recognized as a tumor suppresser in NSCLC. However, the roles of miR-145 during radiotherapy of NSCLC are largely unknown. The present study aimed to investigate the function and underlying mechanism of miR-145 in modulation of radiosensitivity in NSCLC. We generated radioresistant H460 and A549 subclones, named H460R and A549R, respectively, and found that irradiation (IR) could suppress the expression levels of miR-145 in radioresistant NSCLC cells. Furthermore, overexpression of miR-145 could sensitize radioresistant NSCLC cells to IR, whereas knockdown of miR-145 in NSCLC cells acted the converse manner. Mechanically, miR-145 was able to directly target 3'UTR of tropomodulin 3 (TMOD3) mRNA and decrease the expression of TMOD3 at the levels of mRNA and protein. Additionally, we confirmed that miR-145 could enhance the radiosensitivity of radioresistant NSCLC cells by targeting TMOD3 in vitro and in vivo, and could be used as a target in clinical treatment of NSCLC. Collectively, restoration of miR-145 expression increases the radiosensitivity of radioresistant NSCLC cells by suppression of TMOD3, and miR-145 can act as a new radiosensitizer for NSCLC therapy.