miR-654-3p和miR-362-5p调控非小细胞肺癌自噬影响其放射敏感性的作用及机制研究

Radioresistance of non-small cell lung cancer (NSCLC) is a major obstacle in clinical treatment. It has been reported that autophagy and dysregulation of miRNAs are related to radiosensitivity. In preliminary experiments, we found that miR-654-3p and miR-362-5p were significantly upregulated in the tissues of radioresistant patients with lung adenosquamous carcinoma. And upregulation of miR-654-3p and miR-362-5p could promote autophagy by targeting MST1, DDX58 etc., then inhibit apoptosis of NSCLC cells induced by radiation. Our study will firstly investigate the roles of miR-654-3p and miR-362-5p in regulating autophagy and radioresistance, and find their key target genes and critical signaling pathways. Then we will validate their effects in animal models. Eventually we will detect the expressions of miR-654-3p, miR-362-5p and their target genes in NSCLC speciments, and evaluate their clinical significances in radiotherapy of NSCLC. Our study will try to identify the novel pathways for radiosensitization of NSCLC, which would provide scientific evidence for development of new radiosensitizers and individualized radiotherapeutic regimen.

非小细胞肺癌（NSCLC）放射抗拒是临床亟待解决的难题。文献报道肿瘤细胞自噬及miRNAs表达失调能影响肿瘤放射敏感性。前期实验我们发现miR-654-3p和miR-362-5p在肺腺鳞癌放疗抗拒患者组织中表达显著上调；上调miR-654-3p和miR-362-5p可抑制MST1、DDX58等基因的表达，诱导自噬，拮抗放射所致凋亡。本课题将首先证实肺癌细胞中miR-654-3p、miR-362-5p与细胞自噬及放射抗拒之间的关系，确定其作用的关键靶基因及信号通路；然后在动物水平进一步确证；最后利用现有的NSCLC患者病理组织样本检测miR-654-3p、miR-362-5p及其靶基因等的表达，评价其临床应用价值。本研究力求找出调控NSCLC放射敏感性的关键信号通路及其具体分子机制，为研发具有自主知识产权的新型放疗增敏剂提供新靶点，为NSCLC放射治疗个体化方案提供科学新思路。

研究紧扣非小细胞肺癌放射治疗，如何提高非小细胞肺癌的放射敏感性是目前亟待解决的难题。本研究证实了miR-654-3p 、miR-362-5p在放射抗拒 NSCLC患者组织标本中呈高表达；对不同肺癌细胞系进行检测发现miR-654-3p 、miR-362-5p 在放射抗拒株中表达明显高于其亲本细胞，且体内外实验证实抑制miR-654-3p 、miR-362-5p在肺癌细胞株中表达，可显著降低糖酵解水平和放射抗拒性；相反地，过表达miR-654-3p 、miR-362-5p可明显增强肺癌细胞糖酵解水平和降低放射敏感性。首次证实MST1、DDX58分别为 miR-654-3p和miR-362-5p 的直接靶基因，在肺癌细胞糖酵解过程中起到关键调控作用；并对miR-654-3p（miR-362-5p ）/MST1（DDX58）/糖酵解调控轴与肺癌放射敏感性之间的关系进行深层次探索。在本项目资助下，我们的直接研究及拓展研究共发表SCI论文5篇；为临床上肺癌放疗增敏剂的研发及临床应用提供了新的理论依据和新思路。该项目在理论上具有前沿性和创新性，在临床上具有一定实用性及开发潜能。