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

Dan Yu1, Ping Liu1, Ruichen Gao1

  • 1Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Nanjing Medical University, The Second People's Hospital of Changzhou, Changzhou, China.

Journal of Biochemical and Molecular Toxicology
|September 12, 2025
PubMed

Insights

NKX2-1 acts as a tumor suppressor in lung squamous cell carcinoma (LUSC). Lower NKX2-1 levels correlate with poor survival, and its overexpression inhibits LUSC cell growth and metastasis by repressing AKR1B10.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Lung squamous cell carcinoma (LUSC) presents a significant clinical challenge due to poor prognosis and limited therapeutic strategies.
  • The role of NKX2-1, a transcription factor, in LUSC pathogenesis remains incompletely understood.
  • Identifying novel tumor suppressors and their mechanisms is crucial for developing effective LUSC treatments.

Purpose of the Study:

  • To investigate the function of NKX2-1 as a potential tumor suppressor in LUSC.
  • To elucidate the molecular mechanisms underlying NKX2-1's role in LUSC progression.
  • To explore NKX2-1 and its downstream targets as potential therapeutic avenues for LUSC.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) data for NKX2-1 expression and correlation with patient survival.
  • In vitro functional assays including CCK8, colony formation, EdU incorporation, wound healing, and Transwell assays to assess proliferation, migration, and invasion.
  • In vivo studies using a subcutaneous xenograft model to evaluate tumorigenic potential.
  • Transcriptomic analysis and dual-luciferase reporter assays to identify and validate NKX2-1 targets.

Main Results:

  • NKX2-1 expression is significantly downregulated in LUSC tissues compared to lung adenocarcinoma (LUAD) and normal lung tissues, with lower expression linked to poorer survival.
  • Overexpression of NKX2-1 suppressed proliferation, migration, and invasion in LUSC cell lines (SK-MES-1, NCI-H520) and reduced tumor growth in vivo.
  • NKX2-1 directly suppresses AKR1B10 transcription, and this repression is critical for NKX2-1's tumor-suppressive effects in LUSC.

Conclusions:

  • NKX2-1 functions as a tumor suppressor in LUSC by inhibiting cell proliferation, migration, and invasion.
  • The tumor-suppressive activity of NKX2-1 is mediated, at least in part, through the repression of AKR1B10 transcription.
  • Targeting the NKX2-1/AKR1B10 pathway may offer a novel therapeutic strategy for improving outcomes in LUSC patients.
Keywords:
AKR1B10NKX2‐1lung squamous cell carcinomaoverexpressiontumor suppressor

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