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Updated: Jul 10, 2026
Isolation and Characterization of a Head and Neck Squamous Cell Carcinoma Subpopulation Having Stem Cell Characteristics
Published on: May 11, 2016
Identification of an NNK-associated gene signature and tumor microenvironmental features in head and neck squamous
ZiWei Dai1, Junqi Su2, Xiaofeng Shan1
1Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China.; National Center for Stomatology, Beijing, China.; National Clinical Research Center for Oral Diseases, Beijing, China.
Background:
Tobacco exposure is a major risk factor for head and neck squamous cell carcinoma (HNSCC), and the tobacco-specific nitrosamine NNK is an established carcinogen. However, the molecular features linking NNK-associated targets with HNSCC transcriptomic alterations and tumor microenvironmental states remain incompletely understood.
Methods:
NNK-related targets and HNSCC-associated genes were collected from public databases and integrated with GEO transcriptomic datasets. Differential expression analysis, LASSO regression, SHAP interpretation, and external validation were used to identify candidate genes. Immune infiltration analysis, molecular docking, molecular dynamics simulation, comparative docking, single-cell RNA-seq analysis, Human Protein Atlas immunohistochemistry, and western blotting were performed to characterize the prioritized candidate.
Results:
71 overlapping genes were identified between NNK-related targets and HNSCC-associated genes. Integrated analyses retained a six-gene signature comprising MAOB, MMP13, RGS4, ALDH1A1, CXCL8, and PTGS2, which showed diagnostic relevance across validation datasets. Immune deconvolution suggested heterogeneous gene-immune association patterns across the selected genes. Docking suggested that NNK could be accommodated within a predicted MAOB pocket, and 100 ns molecular dynamics simulation supported relative stability of the predicted pose. Single-cell analysis showed that MAOB expression was limited in malignant epithelial cells but relatively enriched in mast cells, glandular cells, keratinocytes, and endothelial cells. Immunohistochemistry and western blotting further supported reduced and heterogeneous MAOB protein expression in HNSCC-related contexts.
Conclusion:
This study identifies a six-gene NNK-associated HNSCC signature and highlights MAOB as a candidate molecular feature associated with tobacco carcinogen-related transcriptomic alterations, immune-context associations, predicted ligand accommodation, and cell-type-specific expression.
Insights
This study identifies a six-gene signature linked to NNK, a tobacco carcinogen, in head and neck squamous cell carcinoma (HNSCC). MAOB is highlighted as a key molecular feature in tobacco-related HNSCC development and its tumor microenvironment.
Area of Science:
- Oncology
- Molecular Biology
- Carcinogenesis
Background:
- Tobacco exposure is a major risk factor for head and neck squamous cell carcinoma (HNSCC).
- NNK, a tobacco-specific nitrosamine, is an established carcinogen, but its molecular links to HNSCC remain unclear.
- Understanding NNK's role in HNSCC transcriptomic and microenvironmental changes is crucial.
Purpose of the Study:
- To identify molecular features linking NNK exposure to HNSCC.
- To characterize the role of NNK-associated genes in HNSCC development and the tumor microenvironment.
- To discover a potential diagnostic signature for NNK-related HNSCC.
Main Methods:
- Integrated analysis of public databases and transcriptomic datasets.
- Differential gene expression, LASSO regression, and SHAP interpretation for candidate gene identification.
- Immune infiltration analysis, molecular docking, molecular dynamics, single-cell RNA-seq, immunohistochemistry, and western blotting for characterization.
Main Results:
- Identified 71 overlapping genes between NNK targets and HNSCC genes.
- Retained a six-gene signature (MAOB, MMP13, RGS4, ALDH1A1, CXCL8, PTGS2) with diagnostic relevance.
- MAOB showed specific expression patterns in immune and stromal cells, with reduced protein levels in HNSCC, and NNK binding potential.
Conclusions:
- A six-gene signature associated with NNK exposure in HNSCC was identified.
- MAOB is highlighted as a potential molecular marker in tobacco carcinogen-related HNSCC.
- The study provides insights into NNK-driven transcriptomic alterations and immune associations in HNSCC.
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