Li Hang, Zhao Shuya, Chen Xin, Feng Guoxing, Chen Zhiyuan, Fan Saijun
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P.R. China.
Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
Carcinogenesis. 2022 Apr 25;43(3):288-296. doi: 10.1093/carcin/bgab121.
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.
放射抗性是在非小细胞肺癌（NSCLC）治疗中遇到的一个主要问题。异常的微小RNA（miRNA）表达参与多种癌症相关信号通路，并深刻影响癌症放疗（RT）的效果。微小RNA-145-5p（miR-145）被认为是NSCLC中的一种肿瘤抑制因子。然而，miR-145在NSCLC放疗过程中的作用在很大程度上尚不清楚。本研究旨在探讨miR-145在调节NSCLC放射敏感性中的功能及潜在机制。我们分别构建了放射抗性的H460和A549亚克隆，命名为H460R和A549R，发现照射（IR）可抑制放射抗性NSCLC细胞中miR-145的表达水平。此外，miR-145的过表达可使放射抗性NSCLC细胞对IR敏感，而在NSCLC细胞中敲低miR-145则产生相反的作用。机制上，miR-145能够直接靶向原肌球蛋白调节蛋白3（TMOD3）mRNA的3'非翻译区（3'UTR），并在mRNA和蛋白质水平降低TMOD3的表达。此外，我们证实miR-145可通过在体外和体内靶向TMOD3增强放射抗性NSCLC细胞的放射敏感性，并且可作为NSCLC临床治疗的一个靶点。总的来说，恢复miR-145表达通过抑制TMOD3增加放射抗性NSCLC细胞的放射敏感性，并且miR-145可作为NSCLC治疗的一种新的放射增敏剂。
