Cancer metastasis leading to the dysfunction of invaded organs is the main cause of the reduced survival rates in lung cancer patients. However, the molecular mechanism for lung cancer metastasis remains unclear. Recently, the increased activity of inflammasome appeared to correlate with the metastatic progression and immunosuppressive ability of various cancer types. Our results showed that the mRNA levels of absence in melanoma 2 (AIM2), one of the inflammasome members, are extensively upregulated in primary tumors compared with normal tissues derived from the TCGA lung adenocarcinoma (LUAD) database. Moreover, Kaplan-Meier analysis demonstrated that a higher mRNA level of AIM2 refers to a poor prognosis in LUAD patients. Particularly, AIM2 upregulation is closely correlated with smoking history and the absence of EGFR/KRAS/ALK mutations in LUAD. We further showed that the endogenous mRNA levels of AIM2 are causally associated with the metastatic potentials of the tested LUAD cell lines. AIM2 knockdown suppressed but overexpression promoted the migration ability and lung colony–forming ability of tested LUAD cells. In addition, we found that AIM2 upregulation is closely associated with an increased level of immune checkpoint gene set, as well as programmed cell death-ligand 1 (PD-L1) transcript, in TCGA LUAD samples. AIM2 knockdown predominantly repressed but overexpression enhanced PD-L1 expression via altering the activity of PD-L1 transcriptional regulators NF-κB/STAT1 in LUAD cells. Our results not only provide a possible mechanism underlying the AIM2-promoted metastatic progression and immune evasion of LUAD but also offer a new strategy for combating metastatic/immunosuppressive LUAD via targeting AIM2 activity.

中文翻译：

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AIM2 上调促进肺腺癌转移进展和 PD-L1 表达

癌症转移导致受侵器官功能障碍是导致肺癌患者生存率下降的主要原因。然而，肺癌转移的分子机制仍不清楚。最近，炎症小体活性的增加似乎与各种癌症类型的转移进展和免疫抑制能力相关。我们的结果表明，与来自 TCGA 肺腺癌 (LUAD) 数据库的正常组织相比，黑色素瘤 2 (AIM2)（炎症小体成员之一）中缺失的 mRNA 水平在原发性肿瘤中被广泛上调。此外，Kaplan-Meier 分析表明，较高的 AIM2 mRNA 水平表明 LUAD 患者的预后较差。特别是，AIM2 上调与吸烟史和无吸烟史密切相关。EGFR/KRAS/ALKLUAD 突变。我们进一步表明，AIM2 的内源性 mRNA 水平与测试的 LUAD 细胞系的转移潜能有因果关系。AIM2 敲低受到抑制，但过表达促进了测试的 LUAD 细胞的迁移能力和肺集落形成能力。此外，我们发现 AIM2 上调与 TCGA LUAD 样本中免疫检查点基因集水平的升高以及程序性细胞死亡配体 1 (PD-L1) 转录本密切相关。AIM2 敲低主要抑制但过表达通过改变 LUAD 细胞中 PD-L1 转录调节因子 NF-κB/STAT1 的活性来增强 PD-L1 表达。