miRNAs调节食管癌放疗敏感性分子机制研究及预测疗效模型的建立

Radioresistance poses a major clinical challenge in esophageal cancer treatment, but the molecular mechanisms of radioresistant remain unclear. miRNAs were involved in DNA damage response (DDR), but most, if not all, human tumors exhibit defects in the DDR and deregulated miRNA expression. Genotoxic agents including UV, X-irradiation, oxidative stress and chemical mutagens, result in a global change on miRNAs expression in a variety of cell types. However, there is no obvious overlap of DNA damage-induced miRNA profiles, suggesting these DNA damage-responsive miRNAs might be cell type-specific. Previous showed that overexpression of miR-200c induces chemoresistant in esophageal cancers mediated through activation of the Akt signaling pathway. Moreover, Let-7c directly repressed cisplatin-activated interleukin (IL)-6/STAT3 prosurvival pathway. But, the regulatory mechanisms of miRNAs in radiosensitivity of esophageal cancer remain elusive. In this study, we established radioresistant esophageal cancer cell lines and used array analysis to compare levels of different miRNAs between radioresistant cell lines and the parental cell lines from which they were derived. The functional miRNAs were determined by multiple studies in cell culture, animal models and in clinical studies. Moreover, a comprehensive model including serum or tissue miRNAs and the prognosis related clinical factors will be established to predict the radiosensitivity. We further explore that the molecular mechanisms of miRNAs regulating radiosensitivity of human esophageal cancer in vitro and in vivo. This study, focusing on the role of miRNA in regulating tumor radiosensitivity, might be improved the individualized therapy, and provided radiosensitive factors and the prognostic molecules that might potentially guide radiotherapy.

食管癌放疗抵抗是临床面临的一个挑战，然而具体的分子机制还不清楚。研究表明miRNAs参与DNA损伤反应(DDR)，但大多数肿瘤都存在DDR缺陷及miRNAs表达的下调，DDR相关miRNAs表达不仅依赖基因组的稳定性，而且还依赖肿瘤组织及病理类型。在食管癌中，miR-200c、Let-7c与食管癌化疗敏感性相关，然而关于miRNAs与食管癌放疗敏感性尚缺乏系统的阐述。本课题拟从食管癌耐放射细胞模型入手，利用miRNAs芯片筛选与食管癌放疗敏感性相关的miRNAs，然后通过细胞水平、临床标本及动物水平三个不同层面研究miRNAs与食管癌放疗敏感性的关系，确定特定功能性miRNAs, 建立预测放疗疗效的miRNAs模型；在DNA损伤反应中，通过对miRNAs靶基因及其转录调控的研究，深入阐述miRNAs调节食管癌放疗敏感性的分子机制，为临床评判食管癌放疗疗效及个体化治疗提供新的靶点。