PO.CL01.16 · 临床研究
凋亡诱导因子线粒体相关蛋白2（AIFM2）在口腔鳞状细胞癌中作为致癌驱动因子和预后生物标志物
Apoptosis-inducing factor mitochondria-associated 2 (AIFM2) functions as an oncogenic driver and prognostic biomarker in oral squamous cell carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
头颈部鳞状细胞癌（HNSCC），包括口腔鳞状细胞癌（OSCC），是一种常见的恶性肿瘤，治疗成效有限。凋亡诱导因子线粒体相关蛋白2（AIFM2），也称为铁死亡抑制蛋白1，已被认为参与铁死亡调控和癌症进展，但其在HNSCC/OSCC中的作用仍不明确。本研究探讨了AIFM2在OSCC中的致癌功能、临床相关性和表观遗传调控。分析了来自TCGA-HNSCC和内部OSCC RNA-Seq数据集的转录组数据，以评估AIFM2表达和临床关联。功能实验检测了AIFM2敲低和过表达对OSCC细胞增殖、迁移、侵袭和药物反应的影响。进行了生物信息学预测、荧光素酶报告基因和miRNA模拟物实验，以识别调控AIFM2的microRNA。采用轻量级梯度提升机（LGBM）模型预测患者死亡风险。高AIFM2表达与HNSCC/OSCC中的晚期分期、低分化、p16阴性和较差生存相关。AIFM2敲低减少了迁移和侵袭，而过表达增强了增殖、迁移和侵袭，但对顺铂、palbociclib或冷大气等离子体的敏感性影响甚微。生物信息学和实验分析确定miR-32-5p和miR-432-5p为AIFM2的直接抑制因子，二者在肿瘤中均下调。AIFM2相关转录本在氧化应激、脂质代谢和E2F靶点相关通路中富集。此外，由LGBM模型生成的AIFM2相关基因表达特征有效地按预后风险对患者进行了分层。总的来说，这些发现表明AIFM2在OSCC中作为致癌驱动因子发挥作用，促进肿瘤进展和不良预后，并受肿瘤抑制性miR-32-5p和miR-432-5p的表观遗传调控，代表一个潜在的预后生物标志物和治疗靶点。
查看英文原文 English abstract
Head and neck squamous cell carcinoma (HNSCC), including oral squamous cell carcinoma (OSCC), is a prevalent malignancy with limited therapeutic success. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2), also known as ferroptosis suppressor protein 1, has been implicated in ferroptosis regulation and cancer progression, yet its role in HNSCC/OSCC remains unclear. This study investigated the oncogenic functions, clinical relevance, and epigenetic regulation of AIFM2 in OSCC. Transcriptomic data from TCGA-HNSCC and in-house OSCC RNA-Seq datasets were analyzed to assess AIFM2 expression and clinical associations. Functional assays examined the effects of AIFM2 knockdown and overexpression on OSCC cell proliferation, migration, invasion, and drug responses. Bioinformatic prediction, luciferase reporter, and miRNA mimic assays were performed to identify microRNAs regulating AIFM2. A Light Gradient Boosting Machine (LGBM) model was employed to predict patient mortality risk. High AIFM2 expression correlated with advanced stage, poor differentiation, p16 negativity, and worse survival in HNSCC/OSCC. AIFM2 knockdown reduced migration and invasion, while overexpression enhanced proliferation, migration, and invasion but had minimal impact on sensitivity to cisplatin, palbociclib, or cold atmospheric plasma. Bioinformatic and experimental analyses identified miR-32-5p and miR-432-5p as direct suppressors of AIFM2, both downregulated in tumors. AIFM2-associated transcripts were enriched in pathways related to oxidative stress, lipid metabolism, and E2F targets. Furthermore, the AIFM2-associated gene expression signature generated by the LGBM model effectively stratified patients by prognostic risk. Collectively, these findings indicate that AIFM2 functions as an oncogenic driver in OSCC, promoting tumor progression and poor prognosis, and is epigenetically regulated by tumor-suppressive miR-32-5p and miR-432-5p, representing a potential prognostic biomarker and therapeutic target.
利益披露 Disclosure
C. Chou, None..
S. Lin, None..
K. Chang, None.