Ding Dong, Liu Hongfei, Zhang Liping, Zhang Guoxin, Wei Yumin, Zhang Wenlong, Yang Xingjiu, Li Mengyuan, Yin Gaofei, Guo Wei, Chen Xiaohong, Huang Zhigang, Gao Ran
Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, PR China; NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, PR China; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing 100021, PR China; Departments of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui Province 230001, PR China.
Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, PR China.
Cell Signal. 2025 Mar;127:111545. doi: 10.1016/j.cellsig.2024.111545. Epub 2024 Dec 3.
Chronic inflammation has been recognized as one of the hallmarks of head and neck squamous cell carcinoma (HNSCC), Absent In Melanoma 2(AIM2) has emerged as important regulators of chronic inflammatory, and participated in initiation, progression of kinds of human cancers. Nonetheless, the biological functions and underlying mechanisms of AIM2 in HNSCC remain inadequately understood. Based on the bioinformatics analysis of public databases, we identified elevated AIM2 expression in HNSCC, which positively correlates with disease stage and HPV infection, thereby possessing both diagnostic and prognostic significance. Immunohistochemistry on clinical samples revealed that AIM2 expression was frequently upregulated in cancerous tissues compared to paracancerous tissues, exhibiting a significant association with Ki-67 expression. Modulating AIM2 expression in HNSCC cell lines through transfection with inhibitors or mimics demonstrated that ectopic AIM2 expression enhances cell growth, migration, tumorigenesis, and metastasis both in vitro and in vivo. A dual luciferase reporter assay indicated that the transcription factor STAT1 can bind directly to the AIM2 promoter region and activate its transcription. The STAT1 inhibitor, fludarabine, reduces AIM2 expression and subsequently diminishes cell proliferation. Mechanistically, AIM2 exerts its tumor-promoting effects through the IL-17-MAPK signaling pathway. Collectively, our data demonstrate that AIM2, transcriptionally activated by STAT1, exhibits oncogenic functions by promoting the IL-17-MAPK signaling pathway, suggesting that AIM2 may be a new intervention targets for the diagnostic and treatment of HNSCC.
慢性炎症已被公认为头颈部鳞状细胞癌（HNSCC）的特征之一，黑色素瘤缺失因子2（AIM2）已成为慢性炎症的重要调节因子，并参与了多种人类癌症的发生和发展。然而，AIM2在HNSCC中的生物学功能和潜在机制仍未得到充分了解。基于公共数据库的生物信息学分析，我们发现HNSCC中AIM2表达升高，这与疾病分期和HPV感染呈正相关，因此具有诊断和预后意义。对临床样本的免疫组织化学分析显示，与癌旁组织相比，癌组织中AIM2表达经常上调，且与Ki-67表达显著相关。通过转染抑制剂或模拟物来调节HNSCC细胞系中AIM2的表达，结果表明异位表达AIM2可在体外和体内增强细胞生长、迁移、肿瘤发生和转移。双荧光素酶报告基因检测表明，转录因子STAT1可直接结合到AIM2启动子区域并激活其转录。STAT1抑制剂氟达拉滨可降低AIM2表达，随后减少细胞增殖。从机制上讲，AIM2通过IL-17-MAPK信号通路发挥其促肿瘤作用。总的来说，我们的数据表明，由STAT1转录激活的AIM2通过促进IL-17-MAPK信号通路发挥致癌功能，这表明AIM2可能是HNSCC诊断和治疗的新干预靶点。
