<i>NKX2‐1</i> Restricts the Growth and Metastasis of Lung Squamous Cell Carcinoma Through Transcriptive Suppression of <i>AKR1B10</i>

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.