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. 2024 Jan-Dec:31:10732748241287904.
doi: 10.1177/10732748241287904.

Comprehensive Analysis Identifies Hyaluronan Mediated Motility Receptor and Cell Division Cycle 25C as Potential Prognostic Biomarkers in Head and Neck Squamous Cell Carcinoma

Hongrui Zhang  1 , Yi Xu  2 , Haijun Han  3 , Xiongwei Ye  1 , Lu Cheng  1 , Yueshuang Shen  1 , Xiaochen Wan  1
Affiliations

Comprehensive Analysis Identifies Hyaluronan Mediated Motility Receptor and Cell Division Cycle 25C as Potential Prognostic Biomarkers in Head and Neck Squamous Cell Carcinoma

Hongrui Zhang et al. Cancer Control. 2024 Jan-Dec.

Abstract

Introduction: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, but its pathogenic mechanisms remain unclear. This study aimed to identify the potential biomarkers underlying the diagnosis and treatment of HNSCC.

Methods: Weighted gene co-expression network analysis (WGCNA) followed by pathway enrichment analysis, analysis of infiltrating immune cells, survival analysis, and methylation analysis were applied to identify the potential hub genes underlying the prognosis of HNSCC. The expression of hub genes was validated by immunofluorescence staining.

Results: A total of 10,274 differentially expressed genes (DEGs) were identified. Through WGCNA, the yellow module (R2 = 0.33, P = 2e-14) was confirmed to be the most significantly associated with the histological grade of HNSCC, and the "Cell Cycle" proved to be the most enriched signaling pathway. Based on the results of survival analysis and immune cell infiltration, 10 hub genes (HMMR, CENPK, AURKA, CDC25C, FEN1, CKS1B, MAJIN, PCLAF, SPC25, and STAG3) were identified. Eight of these (excluding MAJIN and STAG3) were confirmed by performing survival analysis using another dataset (GSE41613). Further, we identified 4 methylation loci in 3 hub genes (cg15122828 and cg20554926 in HMMR, cg12519992 in CDC25C, and cg2655739 in KIAA0101/PCLAF) as being significantly related to survival. Finally, we demonstrated the high mRNA and protein expression of HMMR and CDC25C in HNSCC patients.

Conclusion: Two real hub genes (HMMR and CDC25C) and 3 methylation loci were identified that could potentially serve as prognostic and therapeutic targets for HNSCC, which is significant for studying the pathological mechanisms underlying HNSCC and for developing novel therapies for this disease.

Keywords: HNSCC; TCGA; WGCNA; cell cycle; immune infiltration; survival.

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Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Work flow of this study.
Figure 2.
Figure 2.
Identification of the differentially expressed genes (DEGs) and modules between HNSCC patients and healthy controls in TCGA dataset. (A) Volcano plot of the DEGs between HNSCC patients and healthy controls. FDR <0.05, and |Log2FC| > 1. (B) Cluster dendrogram of all DEGs based on the 1-TOM matrix. (C) Heatmap of the correlation between the module and clinical traits of HNSCC.
Figure 3.
Figure 3.
Functional enrichment analysis. (A) Enriched ontology clusters of genes in the yellow module. (B) The network of enriched ontology clusters colored by cluster.
Figure 4.
Figure 4.
Progression-free survival (PFS) analysis of 10 hub genes in head and neck squamous cell carcinoma (HNSCC). (A-J) Survival analysis of HMMR, CENPK, AURKA, CDC25C, FEN1, CKS1B, MAJIN, PCLAF, SPC25, and STAG3 hub genes in the yellow module. Kaplan-Meier curves showing that patients with different expression levels of the 10 hub genes had different progression-free survival. Data are shown based on the HNSCC samples from TCGA database.
Figure 5.
Figure 5.
The correlations between 5 hub genes (HMMR, CENPK, STAG3, CDC25C, and KIAA0101/PCLAF) and the infiltration of B cells, CD8+ cells, CD4+ cells, macrophages, neutrophils, and dendritic immune cells.
Figure 6.
Figure 6.
Validation of the hub genes by survival analysis in head and neck squamous cell carcinoma (HNSCC). (A-H) Survival analysis of hub genes (HMMR, CENPK, AURKA, CDC25C, FEN1, CSK1B, PCLAF, and SPC25) based on the HNSCC samples from GSE41613. Kaplan-Meier analysis was performed to estimate the overall survival (OS) curves and log-rank test was used to compare the curves. A P-value of <0.05 was considered to indicate statistical significance.
Figure 7.
Figure 7.
Survival plot for the CpGs of hub genes in head and neck squamous cell carcinoma (HNSCC). (A, B) Survival analysis of (A) cg15122828 and (B) cg20554926 CpG sites in HMMR. (C) Survival analysis of cg12519992 CpG site in CDC25C. (D) Survival analysis of cg26155739 CpG site in KIAA0101/PCLAF.
Figure 8.
Figure 8.
Validation of HMMR and CDC25C expression in head and neck squamous cell carcinoma (HNSCC). (A-D) The expression of HMMR and CDC25C in HNSCC based on sample types and tumor grade from UCLCAN. Tumor grade definition: Grade 1indicates well differentiated (low grade), Grade 2 indicates moderately differentiated (intermediate grade), Grade 3 indicates poorly differentiated (high grade), and Grade 4 indicates undifferentiated (high grade). (E) Representative images of HMMR and CDC25C expression in normal control and HNSCC by immunofluorescence staining. (F, G) Statistical analysis of HMMR and CDC25C protein expression by positive area density. *P < 0.05, **P < 0.01.
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