AIM2调控线粒体动态平衡在非小细胞肺癌发生发展中的作用及分子机制研究

Absent in melanoma 2 (AIM2), as a cytoplasmic DNA sensor, plays an important role in innate immunity. Recent studies have shown that AIM2 is also involved in the regulation of the occurrence and progress of cancer. But the intrinsic mechanism is still unclear. Previously, our data showed that the AIM2 was highly expressed in Non-Small Cell Lung Cancer (NSCLC) tissues and cells compared to the normal ones. Moreover, our results demonstrated that AIM2 localizes in mitochondria and regulates mitochondria dynamics. AIM2 inhibition by knockdown significantly suppressed cell proliferation and migration and led to the enhanced mitochondria fusion in NSCLC cells, suggesting that AIM2 might promote the development of NSCLC by regulating the dynamic balance of mitochondrial fusion and fission. Based on the previous work, our project aims at exploring the role and molecular mechanism of high expression of AIM2 in regulating mitochondrial dynamic and promoting the development of NSCLC by using cell and animal models. Meanwhile, we will explore the relationship between the high expression of AIM2 and the occurrence and development of NSCLC in clinic. The completion of this project will be helpful to reveal the new function of AIM2 and to clarify the new mechanism of the development of lung cancer. Our results will provide new targets for the diagnosis and treatment of lung cancer. Our project has important theoretical and clinical significance.

黑色素瘤缺乏因子2（Absent in melanoma 2, AIM2）作为一种细胞内DNA感受器，在固有免疫应答中发挥了重要作用。近年来研究表明AIM2同样参与调控肿瘤的发生与发展,但其内在的作用机制目前尚不清楚。本项目前期发现AIM2在非小细胞肺癌组织细胞中高表达；进一步研究发现AIM2定位于细胞线粒体；敲减AIM2的表达导致线粒体融合增强，细胞增殖受阻和迁移减缓，提示AIM2可能通过调控线粒体融合与分裂的动态平衡进而促进非小细胞肺癌的发生发展。本项目将利用细胞和动物模型深入研究AIM2调控线粒体动态平衡的分子机制及其在非小细胞肺癌发生发展中的作用；同时结合肺癌患者样本，探讨AIM2高表达与非小细胞肺癌间的关系。本项目的完成有助于揭示AIM2的新功能，阐明肺癌发生发展的新机制，为肺癌的诊断和治疗提供新靶点，具有重要的理论和实践意义。

肺癌严重威胁人们的健康和生命安全，深入研究并探索与肺癌发生发展相关的分子靶点及其作用机制，对于肺癌的诊断、治疗及预后评估等都具有重要的意义。本项目中，我们发现黑色素瘤缺乏因子2（Absent in melanoma 2, AIM2）在非小细胞肺癌（NSCLC）组织细胞中高表达。AIM2定位于NSCLC细胞线粒体，并通过调控线粒体融合和分裂的动态平衡进而在体内外促进了NSCLC的发生发展。研究发现，AIM2的高表达与NSCLC病患的生存预后呈显著的负相关。机制研究表明，AIM2以炎症小体非依赖的作用方式促进了泛素连接酶HUWE1对线粒体融合相关蛋白MFN2在154位点赖氨酸的泛素化修饰，促进了MFN2的降解，从而导致线粒体在NSCLC细胞中更多的呈现为分裂态的粒状存在；同时，AIM2通过MFN2调控了线粒体-内质网接触（MAM）的形成与结构，进而影响了细胞内MAPK信号通路的激活。本项目的完成，揭示了NSCLC细胞中线粒体分裂增强、融合减弱的分子机制，揭示了AIM2的新功能和新作用，为肺癌的诊断、治疗及预后评估提供新的潜在靶点。