Lin Yu-Hsuan, Lee Yi-Chen, Liao Jia-Bin, Yu Pei-Lun, Chou Chih-Yu, Yang Yi-Fang
Department of Otolaryngology, Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan, R.O.C.
Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C.
Int J Mol Med. 2025 Apr;55(4). doi: 10.3892/ijmm.2025.5496. Epub 2025 Jan 31.
The adaptation of cancer cells to hostile environments often necessitates metabolic pathway alterations to sustain proliferation and invasion. Head and neck cancer (HNC) has unfavorable outcomes. Therefore, elucidating the functional effects and molecular mechanisms underlying metabolic changes is key. Ingenuity Pathway Analysis identified 'ethanol degradation pathway II and IV' was consistently downregulated in tumor tissue, with aldehyde dehydrogenase 2 () emerging as a key prognostic gene among the top‑ranked differentially expressed metabolic pathways. Immunohistochemistry (IHC) of HNC specimens revealed significant downregulation of ALDH2 expression in tumor tissue, which was inversely correlated with T classification, overall stage, recurrence rate and independently predicted poor prognosis. Functional assays showed that ALDH2 knockdown enhanced HNC cell migration, invasion and colony formation, while ALDH2 overexpression attenuated these processes. Mechanistically, ALDH2 downregulation and subsequent reactive oxygen species (ROS) production in cells activated NF‑κB, upregulating vascular endothelial growth factor C () expression. ALDH2 overexpression inhibited ROS production and the NF‑κB/VEGFC oncogenic pathway, with pharmacological inhibition of NF‑κB and VEGFC mitigating the enhanced migration and invasion of ALDH2‑knockdown HNC cells. IHC and transcriptome analysis further highlighted an inverse association between ALDH2 and VEGFC, with the ALDH2/VEGFC profile predicting the most favorable survival outcome. Inhibition of ALDH2 with Daidzin increased and phosphorylated NF‑κB levels, restoring the migration and invasion of ALDH2‑overexpressing HNC cells by enhancing the effects of VEGFC. Notably, modulating ALDH2 activity using Alda‑1 ameliorated NF‑kB/VEGFC axis upregulation following acetaldehyde treatment, aligning with the aforementioned alterations in alcohol metabolisms. These findings emphasize the key role of ALDH2 in influencing HNC progression and patient outcome, suggesting that targeting the ALDH2/NF‑κB/VEGFC pathway may represent a potential therapeutic strategy for HNC.
癌细胞适应恶劣环境通常需要改变代谢途径以维持增殖和侵袭。头颈癌（HNC）预后不佳。因此，阐明代谢变化背后的功能效应和分子机制是关键。通路分析发现“乙醇降解途径II和IV”在肿瘤组织中持续下调，醛脱氢酶2（ALDH2）在排名靠前的差异表达代谢途径中成为关键的预后基因。对头颈癌标本进行免疫组织化学（IHC）分析显示，肿瘤组织中ALDH2表达显著下调，这与T分期、总体分期、复发率呈负相关，并独立预测预后不良。功能试验表明，敲低ALDH2可增强头颈癌细胞的迁移、侵袭和集落形成，而过表达ALDH2则可减弱这些过程。机制上，ALDH2下调及随后细胞内活性氧（ROS）生成激活了核因子κB（NF-κB），上调了血管内皮生长因子C（VEGFC）的表达。过表达ALDH2可抑制ROS生成及NF-κB/VEGFC致癌途径，对NF-κB和VEGFC的药理学抑制可减轻敲低ALDH2的头颈癌细胞增强的迁移和侵袭。IHC和转录组分析进一步突出了ALDH2与VEGFC之间的负相关，ALDH2/VEGFC图谱预测了最有利的生存结果。用大豆苷元抑制ALDH2可增加NF-κB水平并使其磷酸化，通过增强VEGFC的作用恢复过表达ALDH2的头颈癌细胞的迁移和侵袭。值得注意的是，使用Alda-1调节ALDH2活性可改善乙醛处理后NF-κB/VEGFC轴的上调，这与上述酒精代谢的变化一致。这些发现强调了ALDH2在影响头颈癌进展和患者预后中的关键作用，表明靶向ALDH2/NF-κB/VEGFC途径可能是头颈癌的一种潜在治疗策略。
