LIMD1调控非小细胞肺癌放疗敏感性的机制研究

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.

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。

肺癌是全球最常见的恶性肿瘤之一，其发病率及死亡率均居世界第一。肺癌包括小细胞肺癌和非小细胞肺癌，而又以非小细胞肺癌为主，约占肺癌总人数的85%左右。放射治疗在非小细胞肺癌（NSCLC）中疗效显著，但由于患者放疗敏感性的差异，仍有患者存在放疗抗拒，因此寻找有效预测NSCLC患者放疗敏感性的靶标并探究其机制意义重大！.LIMD1蛋白含3个串联的LIM结构域，属于Ajuba蛋白家族。已报道LIMD1蛋白在非小细胞肺癌中表达下调，并且高表达LIMD1抑制非小细胞肺癌增殖，但是LIMD1是否影响患者的放疗敏感性及可能的机制尚未报道。我们研究证实LIMD1在NSCLC中显著下调，并且发现LIMD1的表达与NSCLC细胞放疗敏感性正相关：过表达LIMD1增加放疗诱导的细胞凋亡及相关凋亡信号通路蛋白的激活，增强NSCLC细胞放疗敏感性；干扰LIMD1则抑制细胞凋亡及相关凋亡信号通路蛋白的激活，导致放疗抗拒。深入研究发现，LIMD1通过其LIM结构域与NF-kB相互作用，并且抑制NF-kB信号通路激活及其下游基因的表达。最后通过裸鼠皮下移植瘤体内实验证实了LIMD1对放疗敏感性的影响。本课题从细胞、分子生物学及裸鼠模型等多方面深入研究LIMD1抑制NF-kB，促进NSCLC放疗敏感性的分子机制，并结合临床分析探讨LIMD1作为预测NSCLC患者放疗敏感性分子靶标的可能性，为NSCLC患者的放射治疗提供新思路。