National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, Shaanxi, China.
Oncogene. 2020 Mar;39(13):2707-2723. doi: 10.1038/s41388-020-1176-9. Epub 2020 Jan 31.
Mitochondrial fusion and fission dynamics fine-tune cellular calcium homeostasis, ATP production capacity and ROS production and play important roles in cell proliferation and migration. Dysregulated mitochondrial dynamics is closely related to tumor development, but the mechanism of mitochondrial dynamics dysregulation and its role in the development of lung cancer remains unclear. Here, we demonstrate that the DNA sensor protein absent in melanoma 2 (AIM2) is highly expressed in non-small cell lung cancer (NSCLC) cells and that high AIM2 expression is associated with poor prognosis in patients with NSCLC. High expression of AIM2 contributes to tumor cell growth and proliferation independent of inflammasome activation in vitro and in vivo. Further studies have shown that AIM2 colocalizes with mitochondria in NSCLC cells and that AIM2 knockdown leads to enhanced mitochondrial fusion and decreased cell proliferation. Mechanistic studies have shown that AIM2 downregulation promotes MFN2 upregulation, thereby enhancing mitochondrial fusion. Moreover, we found that mitochondrial fusion driven by AIM2 knockdown leads to a decrease of cellular reactive oxygen species (ROS) production, which further causes inactivation of the MAPK/ERK signaling pathway. Together, we discovered a novel function of AIM2 in promoting NSCLC development by regulating mitochondrial dynamics and revealed its underlying mechanism. Our work provides new intervention targets for the treatment of NSCLC.
线粒体融合和裂变动力学精细调节细胞内钙稳态、ATP 产生能力和 ROS 产生，并在细胞增殖和迁移中发挥重要作用。失调的线粒体动力学与肿瘤的发展密切相关，但线粒体动力学失调的机制及其在肺癌发展中的作用尚不清楚。在这里，我们证明黑色素瘤缺失蛋白 2（AIM2）在非小细胞肺癌（NSCLC）细胞中高度表达，并且高 AIM2 表达与 NSCLC 患者的预后不良相关。AIM2 的高表达有助于肿瘤细胞的生长和增殖，而不依赖于体外和体内的炎症小体激活。进一步的研究表明，AIM2 在 NSCLC 细胞中与线粒体共定位，并且 AIM2 的敲低导致线粒体融合增强和细胞增殖减少。机制研究表明，AIM2 的下调促进了 MFN2 的上调，从而增强了线粒体融合。此外，我们发现由 AIM2 敲低驱动的线粒体融合导致细胞内活性氧（ROS）产生减少，这进一步导致 MAPK/ERK 信号通路失活。总之，我们发现了 AIM2 通过调节线粒体动力学促进 NSCLC 发展的新功能，并揭示了其潜在的机制。我们的工作为 NSCLC 的治疗提供了新的干预靶点。
