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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Mutations and expression of the NFE2L2/KEAP1/CUL3 pathway in Chinese patients with lung squamous cell carcinoma
Yongxing Zhang1, Hong Fan1, Shuo Fang1
1Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Background:
Recent studies have reported an abnormally high alteration rate in the nuclear factor erythroid 2-like 2 (NFE2L2)/kelch-like ECH-associated protein 1 (KEAP1)/cullin 3 (CUL3) pathway. But the status of this pathway in Chinese patients with lung squamous cell carcinoma (SqCC) has not been thoroughly studied, and there are many uncertainties regarding the expression of pathway intermediates.
Methods:
cDNA sequencing and TaqMan qRT-PCR were carried out in paired cancer and adjacent normal samples obtained from 100 Chinese patients with lung SqCC. Immunohistochemical staining was performed in 50 other paraffin-embedded specimens.
Results:
We detected 47 mutations in 36 patients (36%), and 143 single nucleotide polymorphism (SNP) in 59 patients (59%), of which 41 mutations and 31 SNPs resulted in amino acid (AA) and possibly functional changes. By combining qRT-PCR and immunohistochemistry staining, we confirmed that the expression of NFE2L2 and KEAP1 were highly increased, while the expression of CUL3 was not significantly changed in lung SqCC samples from Chinese patients.
Conclusions:
Considering the frequent mutations and abnormal expression, the NFE2L2/KEAP1/CUL3 pathway may play an important role in the therapy of Chinese patients with lung SqCC.
Insights
The nuclear factor erythroid 2-like 2 (NFE2L2)/kelch-like ECH-associated protein 1 (KEAP1)/cullin 3 (CUL3) pathway shows frequent mutations and altered expression in Chinese lung squamous cell carcinoma (SqCC) patients, suggesting its therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The NFE2L2/KEAP1/CUL3 pathway is frequently altered in various cancers.
- The specific role and expression patterns of this pathway in Chinese lung squamous cell carcinoma (SqCC) remain understudied.
- Uncertainties exist regarding the expression levels of key pathway intermediates in SqCC.
Purpose of the Study:
- To investigate the mutation status and expression levels of the NFE2L2/KEAP1/CUL3 pathway components in Chinese patients with lung SqCC.
- To determine the potential clinical significance of pathway alterations in lung SqCC.
Main Methods:
- cDNA sequencing and TaqMan qRT-PCR were performed on paired tumor and normal samples from 100 Chinese lung SqCC patients.
- Immunohistochemical staining was conducted on 50 paraffin-embedded SqCC specimens.
- Analysis included mutation detection, single nucleotide polymorphism (SNP) identification, and gene expression quantification.
Main Results:
- Mutations were detected in 36% of patients, with 41 mutations potentially altering amino acid sequences.
- 143 SNPs were identified in 59% of patients, 31 of which may have functional consequences.
- NFE2L2 and KEAP1 expression were significantly increased, while CUL3 expression showed no significant change in lung SqCC tissues compared to normal adjacent tissues.
Conclusions:
- The NFE2L2/KEAP1/CUL3 pathway exhibits frequent mutations and abnormal expression in Chinese lung SqCC.
- These findings suggest that the NFE2L2/KEAP1/CUL3 pathway is a potential therapeutic target for lung SqCC in this patient population.
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