CNIH4 as a prognostic biomarker and promoter of malignant progression in head and neck squamous cell carcinoma
- 1Department of Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China
- 2Department of Anatomy, Medical College of Hunan Polytechnic of Environment and Biology
Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is a molecularly heterogeneous malignancy with variable clinical outcomes. Although cornichon family AMPA receptor auxiliary protein 4 (CNIH4) has been implicated in several disease processes, its clinical and biological relevance in HNSCC remains incompletely defined.
Methods: Transcriptomic, genomic, and clinical data from The Cancer Genome Atlas and independent Gene Expression Omnibus cohorts were integrated for bioinformatic analyses. CNIH4 expression was evaluated in relation to diagnostic performance, clinicopathological features, survival, somatic mutations, tumor mutation burden, immune infiltration, immune-regulatory genes, and drug-response profiles. A prognostic nomogram incorporating CNIH4 was also assessed. Functional studies were performed in SAS and SCC-9 oral squamous cell carcinoma cells using two independent CNIH4-targeting siRNAs. Proliferation, colony formation, and wound closure were measured, followed by RNA sequencing and pathway analyses after CNIH4 knockdown.
Results: CNIH4 was consistently overexpressed in HNSCC and validated in three independent cohorts, with retrospective discrimination between tumor and normal tissues in the TCGA-HNSC transcriptomic dataset (AUC = 0.915). Higher CNIH4 expression was associated with unfavorable clinicopathological features and shorter overall survival, disease-specific survival, disease-free interval, and progression-free interval. The nomogram showed moderate prognostic performance, with AUCs of 0.710, 0.750, and 0.720 at 1, 3, and 5 years, respectively. CNIH4 expression was also associated with distinct mutation patterns, higher tumor mutation burden, and differences in bulk transcriptome-derived immune and stromal signatures and immune-regulatory gene expression. Higher CNIH4 expression correlated with lower predicted IC50 values for fluorouracil, tegafur, paclitaxel, and nilotinib. Experimentally, CNIH4 depletion reduced proliferation, colony formation, and wound closure in both cell lines. RNA sequencing revealed changes involving epithelial–mesenchymal transition, interferon signaling, TNF-α/NF-κB signaling, NOTCH signaling, p53-related programs, and the unfolded protein response.
Conclusions: This study suggests that CNIH4 is associated with HNSCC progression-related phenotypes and clinical outcomes. Functional and transcriptomic findings support a functional association between CNIH4 and malignant phenotypes in oral squamous cell carcinoma and justify further investigation of its prognostic and therapeutic relevance in HNSCC.
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BibTeX
@article{chen2026cnih4,
title = {{CNIH4 as a prognostic biomarker and promoter of malignant progression in head and neck squamous cell carcinoma}},
author = {Jun Chen and Aitao Nai and Jijie Cai and Mingchu Liao and Suli Lu and Junyan He},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1963295},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1963295/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - CNIH4 as a prognostic biomarker and promoter of malignant progression in head and neck squamous cell carcinoma
AU - Jun Chen
AU - Aitao Nai
AU - Jijie Cai
AU - Mingchu Liao
AU - Suli Lu
AU - Junyan He
PY - 2026
DA - 2026/10/13
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1963295
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1963295/full
AB - Background: Head and neck squamous cell carcinoma (HNSCC) is a molecularly heterogeneous malignancy with variable clinical outcomes. Although cornichon family AMPA receptor auxiliary protein 4 (CNIH4) has been implicated in several disease processes, its clinical and biological relevance in HNSCC remains incompletely defined. Methods: Transcriptomic, genomic, and clinical data from The Cancer Genome Atlas and independent Gene Expression Omnibus cohorts were integrated for bioinformatic analyses. CNIH4 expression was evaluated in relation to diagnostic performance, clinicopathological features, survival, somatic mutations, tumor mutation burden, immune infiltration, immune-regulatory genes, and drug-response profiles. A prognostic nomogram incorporating CNIH4 was also assessed. Functional studies were performed in SAS and SCC-9 oral squamous cell carcinoma cells using two independent CNIH4-targeting siRNAs. Proliferation, colony formation, and wound closure were measured, followed by RNA sequencing and pathway analyses after CNIH4 knockdown. Results: CNIH4 was consistently overexpressed in HNSCC and validated in three independent cohorts, with retrospective discrimination between tumor and normal tissues in the TCGA-HNSC transcriptomic dataset (AUC = 0.915). Higher CNIH4 expression was associated with unfavorable clinicopathological features and shorter overall survival, disease-specific survival, disease-free interval, and progression-free interval. The nomogram showed moderate prognostic performance, with AUCs of 0.710, 0.750, and 0.720 at 1, 3, and 5 years, respectively. CNIH4 expression was also associated with distinct mutation patterns, higher tumor mutation burden, and differences in bulk transcriptome-derived immune and stromal signatures and immune-regulatory gene expression. Higher CNIH4 expression correlated with lower predicted IC50 values for fluorouracil, tegafur, paclitaxel, and nilotinib. Experimentally, CNIH4 depletion reduced proliferation, colony formation, and wound closure in both cell lines. RNA sequencing revealed changes involving epithelial–mesenchymal transition, interferon signaling, TNF-α/NF-κB signaling, NOTCH signaling, p53-related programs, and the unfolded protein response. Conclusions: This study suggests that CNIH4 is associated with HNSCC progression-related phenotypes and clinical outcomes. Functional and transcriptomic findings support a functional association between CNIH4 and malignant phenotypes in oral squamous cell carcinoma and justify further investigation of its prognostic and therapeutic relevance in HNSCC.
SN - 2234-943X
ER -