AIM2 通过激活 STAT1/NF-κB 促进口腔鳞状细胞癌的辐射抗性、迁移能力和 PD-L1 表达。

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

机构信息

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.

Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan.

出版信息

J Transl Med. 2024 Jan 3;22(1):13. doi: 10.1186/s12967-023-04825-w.

DOI:10.1186/s12967-023-04825-w

PMID:38166970

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10762966/

Abstract

BACKGROUND

Radioresistance and lymph node metastasis are common phenotypes of refractory oral squamous cell carcinoma (OSCC). As a result, understanding the mechanism for radioresistance and metastatic progression is urgently needed for the precise management of refractory OSCC. Recently, immunotherapies, e.g. immune checkpoint inhibitors (ICIs), were employed to treat refractory OSCC; however, the lack of predictive biomarkers still limited their therapeutic effectiveness.

METHODS

The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) databases and RT-PCR analysis were used to determine absent in melanoma 2 (AIM2) expression in OSCC samples. Colony-forming assay and trans-well cultivation was established for estimating AIM2 function in modulating the irradiation resistance and migration ability of OSCC cells, respectively. RT-PCR, Western blot and flow-cytometric analyses were performed to examine AIM2 effects on the expression of programmed death-ligand 1 (PD-L1) expression. Luciferase-based reporter assay and site-directed mutagenesis were employed to determine the transcriptional regulatory activity of Signal Transducer and Activator of Transcription 1 (STAT1) and NF-κB towards the AIM2-triggered PD-L1 expression.

RESULTS

Here, we found that AIM2 is extensively upregulated in primary tumors compared to the normal adjacent tissues and acts as a poor prognostic marker in OSCC. AIM2 knockdown mitigated, but overexpression promoted, radioresistance, migration and PD-L1 expression via modulating the activity of STAT1/NF-κB in OSCC cell variants. AIM2 upregulation significantly predicted a favorable response in patients receiving ICI treatments.

CONCLUSIONS

Our data unveil AIM2 as a critical factor for promoting radioresistance, metastasis and PD-L1 expression and as a potential biomarker for predicting ICI effectiveness on the refractory OSCC.

摘要

背景

放射抵抗和淋巴结转移是难治性口腔鳞状细胞癌（OSCC）的常见表型。因此，迫切需要了解放射抵抗和转移进展的机制，以便对难治性 OSCC 进行精确管理。最近，免疫疗法，如免疫检查点抑制剂（ICI），被用于治疗难治性 OSCC；然而，缺乏预测性生物标志物仍然限制了它们的治疗效果。

方法

利用癌症基因组图谱（TCGA）/基因表达综合数据库（GEO）和 RT-PCR 分析来确定 AIM2 在 OSCC 样本中的表达。集落形成实验和 Trans-well 培养分别用于评估 AIM2 调节 OSCC 细胞辐射抵抗和迁移能力的功能。RT-PCR、Western blot 和流式细胞术分析用于检测 AIM2 对程序性死亡配体 1（PD-L1）表达的影响。荧光素酶报告基因分析和定点突变用于确定转录因子信号转导和转录激活因子 1（STAT1）和 NF-κB 对 AIM2 触发的 PD-L1 表达的转录调控活性。

结果

在这里，我们发现 AIM2 在原发性肿瘤中广泛上调，与正常相邻组织相比，AIM2 是 OSCC 的不良预后标志物。AIM2 敲低减轻，但过表达通过调节 OSCC 细胞变体中的 STAT1/NF-κB 活性，促进放射抵抗、迁移和 PD-L1 表达。AIM2 上调显著预测了接受 ICI 治疗的患者的良好反应。