Yu Dan, Liu Ping, Gao Ruichen, Jiang Ting, Shi Caiwen, Wang Yan, Liu Ming
Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Nanjing Medical University, The Second People's Hospital of Changzhou, Changzhou, China.
Department of Clinical Laboratory, The Third Affiliated Hospital of Nanjing Medical University, The Second People's Hospital of Changzhou, Changzhou, China.
J Biochem Mol Toxicol. 2025 Sep;39(9):e70507. doi: 10.1002/jbt.70507.
Lung squamous cell carcinoma (LUSC) is associated with poor prognosis and limited treatment options. In this study, we investigate the role of NKX2-1 as a tumor suppressor in LUSC. Our analysis of The Cancer Genome Atlas (TCGA) revealed that NKX2-1 expression is significantly lower in LUSC tissues compared to lung adenocarcinoma (LUAD) and normal lung tissues, and patients with low NKX2-1 expression have poorer survival rates. The CCK8, colony formation, EdU incorporation, wound healing, and Transwell assays demonstrated that NKX2-1 overexpression inhibited the proliferation, migration, and invasion of the LUSC cell lines SK-MES-1 and NCI-H520. Moreover, in a subcutaneous xenograft model, NKX2-1 overexpression reduced tumorigenic potential of the injected SK-MES-1 cells. The transcriptomic analysis highlighted the dysregulation of key genes associated with NKX2-1 expression levels. AKR1B10 was expressed at higher levels in LUSC tissues and negatively correlated with NKX2-1. Dual-luciferase assays verified that NKX2-1 suppressed the transcription of AKR1B10 by direct binding to its promoter. The tumor-suppressive effects of NKX2-1 diminished upon AKR1B10 overexpression, which indicated an AKR1B10-dependent mechanism. In sum, our findings indicated that NKX2-1 limited tumor growth and metastasis in LUSC by repressing AKR1B10 transcription, thereby revealing potential therapeutic targets to improve clinical outcomes in these patients.
肺鳞状细胞癌（LUSC）预后较差且治疗选择有限。在本研究中，我们调查了NKX2-1作为LUSC肿瘤抑制因子的作用。我们对癌症基因组图谱（TCGA）的分析显示，与肺腺癌（LUAD）和正常肺组织相比，LUSC组织中NKX2-1表达显著降低，且NKX2-1表达低的患者生存率较差。CCK8、集落形成、EdU掺入、伤口愈合和Transwell实验表明，NKX2-1过表达抑制了LUSC细胞系SK-MES-1和NCI-H520的增殖、迁移和侵袭。此外，在皮下异种移植模型中，NKX2-1过表达降低了注射的SK-MES-1细胞的致瘤潜力。转录组分析突出了与NKX2-1表达水平相关的关键基因的失调。AKR1B10在LUSC组织中表达较高，且与NKX2-1呈负相关。双荧光素酶实验证实，NKX2-1通过直接结合其启动子抑制AKR1B10的转录。AKR1B10过表达后，NKX2-1的肿瘤抑制作用减弱，这表明存在一种依赖AKR1B10的机制。总之，我们的研究结果表明，NKX2-1通过抑制AKR1B10转录来限制LUSC中的肿瘤生长和转移，从而揭示了改善这些患者临床结局的潜在治疗靶点。
