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

Sep 23, 2026

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Lung squamous cell carcinoma (LUSC) is linked to unfavorable prognosis and limited therapeutic options. This study examines NKX2-1 as a tumor suppressor in LUSC. TCGA analysis shows NKX2-1 expression is markedly reduced in LUSC versus LUAD and normal lung tissues, and low NKX2-1 predicts worse survival. Overexpression assays indicate NKX2-1 restrains proliferation, migration, and invasion, and reduces tumorigenicity in a xenograft model. Mechanistically, NKX2-1 transcriptionally represses AKR1B10 via promoter binding, and restoring AKR1B10 reverses NKX2-1’s anti-tumor effects, highlighting an AKR1B10-dependent axis and potential targets to improve outcomes.

LanguageEnglish

CategoryHealthcare

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Abstract

Introduction

Journal of Biochemical and Molecular Toxicology RESEARCH ARTICLE NKX2‐1 Restricts the Growth and Metastasis of Lung Squamous Cell Carcinoma Through Transcriptive Suppression of AKR1B10 Dan Yu1 | Ping Liu1 | Ruichen Gao1 | Ting Jiang1 | Caiwen Shi1 | Yan Wang2 | Ming Liu1,3 1Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Nanjing Medical University, The Second People's Hospital of Changzhou, Changzhou, China | 2Department of Clinical Laboratory, The Third Affiliated Hospital of Nanjing Medical University, The Second People's Hospital of Changzhou, Changzhou, China | 3Changzhou Medical Center, Nanjing Medical University, Changzhou, China Correspondence: Yan Wang ([13770923431@163.com](13770923431@163.com)) | Ming Liu ([2306051553@qq.com](2306051553@qq.com); [hxklming@163.com](hxklming@163.com)) Received: 15 May 2025 | Revised: 11 August 2025 | Accepted: 2 September 2025 Funding: This work was supported by the Changzhou Medical Center and the Outstanding Talent of Changzhou “The 14th Five‐Year Plan” High‐Level Health Talents Training Project (2022CZBJ056) and the Science and Technology Project of Changzhou Health Commission (ZD202337) . Keywords: AKR1B10 | lung squamous cell carcinoma | NKX2‐1 | overexpression | tumor suppressor ABSTRACT 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. 1 | Introduction Non‐small cell lung cancer (NSCLC) is the most common type of lung cancer, and its subtypes include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma [1]. Lung squamous cell carcinoma (LUSC), which originates from the squamous cells lining the airways, usually occurs in the central parts of the lungs, near the bronchi [2]. It is strongly associated with smoking, particularly in male smokers, and it often causes symptoms like chronic cough and hemoptysis. There are a few unique challenges in treating LUSC. It tends to be diagnosed only at an advanced stage due to its association with smoking and the presence of symptoms like chronic cough and hemoptysis. There is often resistance to conventional chemotherapy and radiotherapy, which decreases the response rate and shortens the duration of remission, and toxicity and side effects are frequently encountered [3–8]. Effective targeted therapies are few, and the patients often do not respond well to immunotherapy. Ongoing research is essential to | Dan Yu and Ping Liu contributed equally to this work and should be considered co‐first authors. | | --- | | This is an open access article under the terms of the Creative Co

FAQs

What did TCGA analysis show about NKX2-1 in lung squamous cell carcinoma?

NKX2-1 expression was significantly lower in LUSC tissues than in lung adenocarcinoma and normal lung tissues, and patients with low NKX2-1 had poorer survival.

How does NKX2-1 overexpression affect LUSC cells and tumor behavior?

NKX2-1 overexpression inhibited proliferation, migration, and invasion of SK-MES-1 and NCI-H520 cells and reduced tumorigenic potential in a subcutaneous xenograft model.

What mechanism links NKX2-1 to AKR1B10 and the anti-tumor effects?

NKX2-1 suppressed AKR1B10 transcription by directly binding its promoter; overexpressing AKR1B10 diminished NKX2-1’s tumor-suppressive effects, indicating an AKR1B10-dependent mechanism.

Sep 23, 2026

Uploaded by Franzy