NKX2-1 Restricts the Growth and Metastasis of Lung Squamous Cell Carcinoma Through Transcriptive Suppression of AKR1B10

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.