LIMD1调控非小细胞肺癌放疗敏感性的机制研究

项目名称： LIMD1调控非小细胞肺癌放疗敏感性的机制研究

项目编号： No.81502660

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 吴志强

作者单位： 天津医科大学

项目金额： 18万元

中文摘要： 放射治疗是非小细胞肺癌(NSCLC)主要治疗手段之一，但由于放疗敏感性不同，患者对放疗存在显著的个体化差异，因此研究调控放疗敏感性的靶标并阐明其机制对于指导临床个体化放疗尤为重要。本课题组前期研究发现：LIMD1在NSCLC中显著下调，且其表达与NSCLC细胞放疗敏感性正相关。过表达LIMD1增加细胞放疗敏感性，干扰LIMD1则导致放疗抗拒。进一步研究发现，LIMD1可抑制NF-kB信号通路，进而促进放疗诱导的细胞凋亡和自噬性死亡，增加放疗敏感性，但LIMD1如何调控NF-kB信号通路进而影响放疗敏感性需深入研究。本项目将在前期基础上，从分子、细胞、模型小鼠及临床患者四个方面深入研究LIMD1如何调控NF-kB信号通路进而影响放疗敏感性的分子机制，并探讨LIMD1作为预测NSCLC患者放疗敏感性分子靶标的可能性。本课题的开展将为NSCLC的放射治疗提供新思路、新靶点，具有重要临床意义。

中文关键词： 非小细胞肺癌；放疗敏感性；LIMD1；凋亡；自噬性细胞死亡

英文摘要： Radiotherapy is one of the main treatments for non-small cell lung cancer (NSCLC). However, due to the different radiosensitivities in different patients, the therapeutic responses vary dramaticallyfrom one to another. Thus, it is of great importance to identify biomarkers for predicting radiosensitivity of patients and to uncover the underlying mechanisms for individualized radiotherapy. Our preliminary data showed that LIMD1 was significantly downregulated in NSCLC and its expression positively correlated with radiosensitivity of NSCLC cells. Overexpression of LIMD1 sensitized NSCLC cells to radiation, while knockdown LIMD1 led to radiation resistant. Further study revealed that LIMD1inhibited NF-kB signaling, and subsequently resulted in enhancement of radiation- induced apoptosis and autophagic cell death. However, much more exact molecular mechanisms about how LIMD1 inhibited NF-kB signaling and radiosensitized NSCLC remain to be further investigated. Hence, based on these findings, this project will deeply investigate the mechanisms of LIMD1 in inhibiting NF-kB signaling and sensitizing NSCLC to radiation by employing molecular biology, cell biology techniques, nude mice xenograft models and clinical species. And also we will investigate the potential of LIMD1 as a marker for patients radiosensitivty predicting. All in all, this research would provide us new target and therapeutic strategy for improving the radiotherapy outcome of NSCLC patients, which is of great clinical significance.

英文关键词： Non-small cell lung cancer;Radiosensitivity;LIMD1;Apoptosis;Autophagic cell death