AIM2 upregulation promotes metastatic progression and PD‐L1 expression in lung adenocarcinoma

Abstract

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.

AIM2 promotes irradiation resistance, migration ability and PD-L1 expression through STAT1/NF-κB activation in oral squamous cell carcinoma

“…AIM2 upregulation was found to predict a favorable prognosis in colorectal cancer [ 7 , 8 ], gastric cancer [ 9 ] and osteosarcoma [ 10 ], but associated with cancer progression, e.g. tumor growth, metastasis and immunosuppression, in non-small cell lung cancer [ 13 , 14 ], melanoma [ 15 ], triple-negative breast cancer [ 16 ] and renal cell carcinoma [ 17 ]. AIM2 upregulation due to promoter hypomethylation has been shown to play an oncogenic role [ 26 ] and the enforced expression of AIM2 promoted tumor growth and lymph node metastasis in OSCC [ 18 , 19 ].…”

“…Trans-well cultivation was performed by Boyden Chamber Assay (NeuroProbe, Gaithersburg, MD, USA) according to the procedure as shown in our previous report [ 14 ]. For neutralization of IL-1β, AIM2-overexpressing SAS cells (1.5 × 10 4 ) were pre-treated without or with rabbit anti-IL-1β (#41,059, SAB, Greenbelt, MD, USA) and non-immunized control (#10,119-T52/#CR1, Sino Biological, Beijing, China) polyclonal antibodies at 10 μg/ml for 24 h before the trans-well culture for 16 h. Giemsa solution was used to stain the migrated cells after the removal of non-migrated cells.…”

“…The loss of AIM2 also promoted hepatocarcinoma progression through activation of the mTOR-S6K1 pathway [ 11 ] and EMT process [ 12 ]. In contrast, AIM2 upregulation promoted cell growth, metastasis and immunosuppression through the inflammasome-dependent pathway and correlated with poor survival in non-small cell lung cancer [ 13 , 14 ], melanoma [ 15 ] and triple-negative breast cancer [ 16 ]. Besides, AIM2 was found to trigger renal cell carcinoma progression and sunitinib resistance through FOXO3a-ACSL4 axis-regulated ferroptosis [ 17 ].…”