Identification of Novel Therapeutic Targets for Head and Neck Squamous Cell Carcinoma Through Bioinformatics Analysis

doi:10.21203/rs.3.rs-4614762/v1

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Identification of Novel Therapeutic Targets for Head and Neck Squamous Cell Carcinoma Through Bioinformatics Analysis

https://doi.org/10.21203/rs.3.rs-4614762/v1

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Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous cancer with limited therapeutic options. Using publicly available datasets, we identified the WD repeat domain 54 (WDR54) gene as a potential therapeutic target in HNSCC. Gene Expression Profiling Interactive Analysis version 2 (GEPIA2) was used to identify genes differentially overexpressed in HNSCC. Our results showed that WDR54, a member of the WD40 repeat domain family, was overexpressed in HNSCC tumor samples. Analysis of three Gene Expression Omnibus datasets showed that WDR54 was overexpressed in tumor samples. Using the UALCAN database, we showed that WDR54 expression in patients with HNSCC at different tumor stages gradually increased with disease progression. We confirmed the association between WDR54 and metastasis using TNMplot.com. WDR54 was overexpressed in metastatic samples compared to that in normal and tumor samples. Kaplan–Meier analysis showed that patients with high WDR54 levels had a poorer prognosis. Additionally, WDR54 expression was correlated with the epidermal growth factor receptor, which is frequently overexpressed in HNSCC. Our findings suggest that WDR54 is a promising biomarker and therapeutic target in HNSCC.

Biological sciences/Cancer

Biological sciences/Molecular biology

Head and neck squamous cell carcinoma

WD repeat domain 54

Gene Expression Profiling Interactive Analysis web server

Gene Expression Omnibus

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide [1]. The key factors contributing to HNSCC carcinogenesis include tobacco use and human papillomavirus (HPV) infection [2]. Cornerstone treatments for HNSCC include surgery, radiotherapy, and chemotherapy. However, these interventions often result in significant morbidity and do not sufficiently address the high rates of metastasis and recurrence. Despite advances in therapeutic techniques, the estimated 5-year survival rate of patients with HNSCC remains below 50% [3]. This stagnation in therapeutic advancements highlights the urgent need for novel diagnostic and therapeutic strategies for the management of HNSCC.

Biomarkers have revolutionized oncological diagnostics and therapies, creating new opportunities for personalized treatment regimens. In HNSCC, as in other malignancies, identifying accurate biomarkers is critical for the early detection, prediction of disease progression, and response to therapy [4]. However, the discovery of effective tailored treatments for HNSCC has been impeded by a lack of knowledge regarding the molecular mechanisms that promote tumor growth and resistance to treatment.

Recent advancements in bioinformatics have revolutionized cancer research by providing tools that can systematically analyze vast datasets to uncover potential genetic drivers of cancer. This approach is particularly promising for the identification of novel therapeutic targets specific to the genetic landscape of individual cancers. The Gene Expression Profiling Interactive Analysis version 2 (GEPIA2) is a web server that provides robust gene expression profiling and is instrumental in advancing our understanding of cancer biology [5]. Our study leveraged the capabilities of GEPIA2 to investigate WD repeat domain 54 (WDR54), which has previously been underexplored in the context of HNSCC.

The WDR domain is composed of a seven-bladed ß-propeller structure that ends with a tryptophan-aspartic acid dipeptide composed of 40 amino acids. The WDR domain is one of the most abundant protein-protein interaction (PPI) domains [6]. PPIs play various roles in cell cycle regulation [7, 8], signal transduction [9], and apoptosis [10]. Several WDR domains have been implicated in carcinogenesis [11–13] and metastasis in various cancers, such as gastric, lung, and prostate cancers. With the expanding understanding of PPIs, the human protein interactome is increasingly being recognized as a rich source of potential targets for disease treatment [14, 15]. WDR54 plays an oncogenic role in bladder and colon cancers and T-cell acute lymphoblastic leukemia [16–18].

Although WDR domains have been studied in various cancer types, their roles in HSNCC have not yet been investigated. We conducted a comprehensive analysis of the biological functions of WDR54 in HNSCC using GEPIA2 and the Gene Expression Omnibus (GEO) database. We observed that WDR54 was overexpressed in HNSCC and associated with poor patient survival. These findings suggest that WDR54 is a potential prognostic biomarker and therapeutic target for patients with HNSCC.

The purpose of this study was to use bioinformatic methods to fully characterize the expression of WDR54 in HNSCC and assess its potential as a therapeutic target. By defining the role of WDR54 in the pathophysiology of HNSCC, we expect to contribute to the development of more precise and successful treatment options, thereby improving patient outcomes for this challenging disease.

WDR54 expression is upregulated in HNSCC

We used GEPIA2 to search for genes that were commonly expressed as part of the survival-related gene category (n = 500) and genes that were differentially expressed (n = 2077) between normal and HNSCC tumor tissues using the prostate adenocarcinoma (TCGA-PRAD) and Genotype-Tissue Expression (GTEx) datasets accessed from the Cancer Genome Atlas. We identified 50 genes that were commonly overexpressed in both differential expression and survival analyses of HNSCC. We selected WDR54 and analyzed the effect on HNSCC (Fig. 1). Using the GEPIA2 database, we compared 519 normal and 44 tumor samples. WDR54 was overexpressed in most tumors compared to that in normal tissues, particularly lymphoid neoplasm diffuse large B cell lymphoma (DLBC), esophageal carcinoma (ESCA), kidney chromophobe (KIRC), kidney renal clear cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), skin cutaneous melanoma (SKCM), thymoma (THYM), and head and neck squamous cell carcinoma (HNSC) (Fig. 2A). A comparison of WDR54 mRNA expression in 44 normal and 519 HNSCC tumor tissues revealed significant overexpression in tumor tissues (Fig. 2B). We used the GSE58911, GSE178537, and GSE33232 datasets to analyze WDR54 expression and observed that it was significantly elevated in tumors compared to that in normal samples in all three analyses (Fig. 2C).

WDR54 levels and clinical characteristics of patients with HNSCC

The expression of WDR54 in various patient groups was evaluated using the online UALCAN database. Compared with normal tissues, WDR54 was overexpressed in HNSCC tissues (Fig. 3A).

We compared WDR54 expression levels between the normal group and different pathological stages. WDR54 levels were observed to increase with cancer stage (stages 1, 2, 3, and 4) in patients with HNSCC compared to those in normal tissues (Fig. 3B). WDR54 expression was higher in HNSCC tissues classified as cancer stages 1, 2, 3, and 4 than that in normal tissues (Fig. 3C). In the case of nodal metastasis, the expression of WDR54 at all stages (N0, N1, N2, and N3) was higher than that in normal tissues (Fig. 3D).

WDR54 expression in HNSCC metastasis

Our RNA-seq-based TNM.plot analysis confirmed the overexpression of WDR54 in HNSCC tumor samples compared to that in normal samples (Fig. 4A). We observed that WDR54 expression was further increased in metastatic patient samples compared to that in normal samples (Fig. 4B). Additionally, we analyzed WDR54 expression using several GEO datasets (GSE178537, GSE117753, and GSE67614) and observed that metastatic samples had significantly higher WDR54 levels than that in normal and tumor samples (Fig. 4C).

Prognostic value of WDR54 levels in HNSCC

To further clarify the relationship between WDR54 expression and the prognosis of patients with HNSCC, we used the GEPIA2 database and Kaplan–Meier survival curve analysis. Using a survival map from the GEPIA2 database, we analyzed the expression of genes in various cancer types and observed that increased WDR54 expression was associated with poor survival in patients with adrenocortical carcinoma, acute myeloid leukemia, liver hepatocellular carcinoma, mesothelioma, uveal melanoma, and HNSCC (Fig. 5A).

An overall survival graph obtained using the GEPIA2 database confirmed that WDR54 overexpression was associated with poor survival (p = 0.00023, hazard ratio [HR] (high) = 2.1, p (HR) = 0.00031) (Fig. 5B). Similar to the GEPIA2 database, the Kaplan–Meier plotter analysis showed that patients with high WDR54 expression had lower survival rates, with a median overall survival of 61.27 months for WDR54 low expression and 32.83 months for WDR54 high expression (p = 0.0031, HR = 1.49) (Fig. 5C). We analyzed the survival rates according to tumor stage and WDR54 levels. When we checked by pathological stage, we observed that a high WDR54 level was associated with poor survival in stages 1 + 2, 3, and 4 (Fig. 5D-5F). Although the results were not significant when stages 1 and 2 were examined separately, high WDR54 levels were associated with poor survival (data not shown).

Patients with high WDR54 levels had lower survival rates than those with low WDR54 levels at all stages. The survival rates decreased gradually with high WDR54 levels at various tumor stages, progressing from 85.67 months for stage 1 + 2 (p = 0.059, HR = 2.67), to 32.83 months for stage 3 (p = 0.046, HR = 2.37), and finally declining to 30.5 months for stage 4 (p = 0.026, HR = 1.52). When analyzed by sex, both men and women with higher WDR54 levels had lower survival rates (Supplementary Fig. S1A, S1B). Survival rates were 35.97 months for men and 25.43 months for women with high WDR54 levels.

We observed a significant correlation between WDR54 expression and the immune subtype in HNSCC. We performed a Kaplan–Meier survival analysis by stratifying the active immune subtypes. Patients with high WDR54 levels had a poor prognosis, regardless of whether they had enriched or decreased levels of macrophages, natural killer T cells, CD4 + memory T cells, or CD8 + T cells (Fig. 6 and Supplementary Fig. S2).

Correlation between WDR54 and epidermal growth factor receptor (EGFR) expression

We used the GEPIA2 online tool to analyze the correlation between the human EGFR and WDR54 proteins, which are target biomarkers for head and neck cancer and various other cancers. We observed that both genes were overexpressed in tumors compared to those in normal tissues in the DLBS, ESCA, GBM, KIRC, KIRP, LGG, LUSC, PAAD, STAD, THYM, and HNSCC gene expression datasets. (Fig. 7A). Moreover, WDR54 expression was positively correlated with EGFR expression in HNSCC (Fig. 7B). We further examined the expression of WDR54 and EGFR using two different GEO datasets (GSE58911 and GSE178537). Both datasets indicated that WDR54 expression was significantly correlated with EGFR expression (Fig. 7C).

HNSCC is a highly heterogeneous cancer characterized by an aggressive disease course, a high recurrence rate, a low response to treatment, and a low survival rate, leading to a need for research on its pathogenesis and new therapeutic agents.

We accessed the publicly available GEPIA2 web server to identify differentially overexpressed genes in HNSCC and analyzed various GEO datasets to identify novel therapeutic targets for head and neck cancer. We screened several candidate genes using GEPIA2 and selected WDR54 for further analysis. WDR54 is a member of the WD40 repeat-domain family. WDR is a PPI domain [28, 29] that plays diverse roles in cell cycle regulation [7, 8], signal transduction [9], and apoptosis [10], and several WDR domains have been implicated in carcinogenesis [11–13].

In the current study, we examined the expression of WDR54, a post-translationally modified WDR domain protein [30]. WDR54 plays an oncogenic role in various cancers, and our data support its potential as a novel therapeutic target and biomarker for head and neck cancer, based on our analysis of the GEPIA2, GEO, and UALCAN gene expression datasets [16–18].

We observed that WDR54 expression was significantly higher in patients with HNSCC than that in healthy individuals. Using TNMplot.com, a web tool for normal, tumor, and metastatic tissue gene expression, we compared tumor and metastatic samples to show that WDR54 was overexpressed in metastatic samples compared to that in tumor samples. This result was confirmed by analyses using the GEO HNSCC datasets. Together, these findings suggest that WDR54 overexpression contributes to cancer progression and metastasis in HNSCC cells.

We used GEPIA2 and Kaplan–Meier analyses to determine whether high WDR54 expression was associated with HNSCC survival. Our overall survival analysis using both GEPIA2 and Kaplan–Meier analyses showed that high WDR54 expression levels were associated with poor survival outcomes in patients with HNSCC, regardless of sex, disease stage, immune subtype enrichment, or depletion. These findings suggest that WDR54 is a potential novel therapeutic target for HNSCC.

EGFR is an oncogene that affects gene expression, proliferation, angiogenesis, apoptosis inhibition, cell motility, metastasis, adhesion, and angiogenesis. HNSCC is a highly heterogeneous disease characterized by the overexpression of EGFR. Over 90% of the patients with HNSCC overexpressing EGFR have a shorter survival period, which is one of the reasons why cetuximab, which targets EGFR, is used to treat HNSCC [31]. We analyzed the correlation between WDR54 and EGFR to explore their potential as novel biomarkers and therapeutic candidates for HNSCC. WDR54 has been identified as a new oncogene in colon and bladder cancers; however, its molecular mechanism and functional association with other molecules involved in tumor cell growth are unknown. WDR54 is cross-linked by transglutaminase 2 and activates the EGFR-mediated signaling pathway that regulates tumorigenesis [32].

We observed a positive correlation between EGFR and WDR54 expression in HNSCC cells. Our analysis using only tumor samples showed a robust correlation between EGFR and WDR54, suggesting that WDR54 may act as an oncogene and regulator of EGFR expression in HNSCC.

Previous studies have reported the role of WDR54 in several cancers; however, its function in HNSCC remains poorly understood. Based on a comprehensive analysis of publicly available gene expression datasets, we propose WDR54 as a potential new biomarker and therapeutic target for HNSCC. However, further experimental studies are required to elucidate the function and molecular mechanism of action of WDR54 in HNSCC. Such studies will provide a better understanding of the role of WDR54 in HNSCC and lead to the development of novel therapeutic strategies for this disease.

Gene Expression Profiling Interactive Analysis version 2 (GEPIA2)

To quantitatively assess WDR54 expression in various tissues and its association with clinical outcomes in HNSCC, we used the GEPIA2 platform, an advanced online resource designed for comprehensive analysis of RNA sequencing data. Hosted at “gepia2.cancer-pku.cn,” this tool facilitates robust and detailed investigations of gene expression patterns by integrating data from two major databases: The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project [5, 19].

The Gene Expression Ominibus database

The National Center for Biotechnology Information (NCBI) GEO database (http://www.ncbi.nlm.nih.gov/geo/) is a publicly available resource containing a wealth of high-throughput functional genomic data. The data used in our analysis were obtained from the NCBI-GEO database by searching for the keywords “Head and neck squamous cell carcinoma” and “homo sapiens,” and the datasets GSE33232, GSE 58911, GSE178537, GSE 117753, and GSE 67614 were used for analysis (Table 1).

Table 1

*Homo sapiens* data in the Gene Expression Omnibus (GEO) for head and neck squamous cell carcinoma [20–24]
Reference	GEO	Platform	Sample	Normal	Tumor	Metastasis
Stansfield JC et al. [20]	GSE 33232	GPL5175	Head and neck squamous cell carcinoma	25	44
Lobert S et al. [21]	GSE 58911	GPL6244	Head and neck squamous cell carcinoma	15	15
Cheng HY et al. [22]	GSE 178537	GPL16791 GPL18573	Head and neck squamous cell carcinoma	20	19	9
Kondratyev M et al. [23]	GSE 117753	GPL10558	Head and neck squamous cell carcinoma		9	9
Ding L et al. [24]	GSE 67614	GPL7363	Head and neck squamous cell carcinoma		72	27

Kaplan–Meier plotter analysis

The Kaplan–Meier plotter (http://kmplot.com/analysis/) enables the assessment of the relationship between the expression of all genes (mRNA, miRNA, Protein, and DNA) and tumor survival using data from > 35,000 samples across 21 different types of cancer [20–25].

UALCAN

UALCAN (http://ualcan.path.uab.edu/) is a publicly accessible web-based platform that enables the analysis of cancer omics data, with a particular focus on tumor gene expression and survival analysis [26].

TNMplot

TNM plot (http://www.tnmplot.com/) is an online tool that conducts differential gene expression analysis of tumor, normal, and metastatic tissues. Moreover, it utilizes data from 56,938 unique samples, including 15,648 normal, 40,442 tumors, and 848 metastatic samples collected from the GEO, GTEx, TCGA, and TARGET databases [27].

Conflict of interest statement:

The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study.

Funding:

This work was supported by the Korea Medical Device Development Fund grant funded by the Korean government (the Ministry of Science and ICT, Ministry of Trade, Industry and Energy, Ministry of Health & Welfare, and Ministry of Food and Drug Safety) (Project Number: RS-2020-KD000027), and by the Global–Learning & Academic Research Institution for Master’s· PhD students and the Postdocs (LAMP) Program of the National Research Foundation (NRF) of Korea grant funded by the Ministry of Education (Grant Number: RS-2023-00301914).

Author Contribution

Conceptulization, E.-J.J., E.J.K. and Y.S.K.; Methodology, E.-J.J. and E.J.K.; Software, E.-J.J., and E.J.K. ; Validation, E.-J.J. and E.J.K.; Formal analysis, E.-J.J. and E.J.K.; Investigation, E.-J.J. and E.J.K.; Resources, E.-J.J. and E.J.K.; Data curation, E.-J.J. and E.J.K.; Writing-original draft preparation, E.-J.J.; Writing-review and editing, E.J.K. and Y.S.K.; Visualization, E.-J.J. and E.J.K.; Supervision, Y.S.K.; Project administration, Y.S.K.; Funding acquisition, Y.S.K.; All authors have read and agreed to the published version of the manuscript.

Acknowledgments

This work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, Ministry of Trade, Industry and Energy, Ministry of Health & Welfare, and Ministry of Food and Drug Safety) (Project Number: RS-2020-KD000027), and by the Global - Learning & Academic Research Institution for Master’s·PhD students, and Postdocs (LAMP) Program of the National Research Foundation (NRF) of Korea grant funded by the Ministry of Education (Grant Number: RS-2023-00301914).

Data Availability

All data used in this study were obtained from publicly available data tools, including GEPIA2, The Gene Expression Omnibus database, Kaplan-Meier plotter, UALCAN, and TNMplot.

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No competing interests reported.

OnlineSupplementaryFigure1.png
Supplementary Figure S1. Investigating the impact of WDR54 expression on survival based on gender in HNSCC using Kaplan–Meier analysis (A: Male, log-rank P = 0.0016, HR = 1.68; B: Female, log-rank P = 0.05, HR = 1.67). HR: hazard ratio
OnlineSupplementaryFigure2.png
Supplementary Figure S2. Investigating the impact of WDR54 expression on survival based on decreased immune subtypes in HNSCC using Kaplan–Meier analysis. (A: macrophages-decreased, log-rank P = 0.0043, HR = 1.72; B: natural killer T cells-decreased, log-rank P = 0.0011, HR = 1.72; C: CD⁺ memory T cells-decreased, log-rank P = 0.047, HR = 1.68; D: CD8⁺ T cells-decreased, log-rank P = 0.093, HR = 1.47)

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You are reading this latest preprint version

Identification of Novel Therapeutic Targets for Head and Neck Squamous Cell Carcinoma Through Bioinformatics Analysis

Status:

Version 1

Abstract

Figures

Introduction

Results

WDR54 expression is upregulated in HNSCC

WDR54 levels and clinical characteristics of patients with HNSCC

WDR54 expression in HNSCC metastasis

Prognostic value of WDR54 levels in HNSCC

Correlation between WDR54 and epidermal growth factor receptor (EGFR) expression

Discussion

Conclusion

Material and Methods

Gene Expression Profiling Interactive Analysis version 2 (GEPIA2)

The Gene Expression Ominibus database

Kaplan–Meier plotter analysis

UALCAN

TNMplot

Declarations

Conflict of interest statement:

Funding:

Author Contribution

Acknowledgments

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1