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Article Open Access

Dual faces of AREG in OSCC: Reduced circulating levels and enhanced tumor expression suggest compartmentalized regulation

  • Authors:
    • Neha Kumari
    • Charmi Jyotishi
    • Mansi Patel
    • Reeshu Gupta
  • View Affiliations / Copyright

    Affiliations: Parul Institute of Applied Sciences, Parul University, Vadodara, Gujarat 391760, India, Research and Development Cell, Parul University, Vadodara, Gujarat 391760, India
    Copyright: © Kumari et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 6
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    Published online on: December 18, 2025
       https://doi.org/10.3892/wasj.2025.421
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Abstract

Oral squamous cell carcinoma (OSCC) remains a major global health concern due to its aggressive behavior and poor clinical outcomes, particularly in advanced, technically unresectable cases. The present study adopted a comprehensive multi‑omics approach to identify potential biomarkers and therapeutic targets involved in the progression of OSCC. Differential gene expression analysis revealed 794 upregulated and 1,331 downregulated genes, with 16 genes significantly associated with both overall and disease‑free survival. Among these, amphiregulin (AREG) and C‑X3‑C motif chemokine receptor 1 (CX3CR1) were identified through receiver operating characteristic analysis as the only two genes with a meaningful association with T4 tumor stage (AREG, upregulated; CX3CR1, downregulated), warranting further investigation. Epigenetic profiling revealed that copy number deletions and methylation changes in CX3CR1 were linked to a decreased expression, supporting its tumor‑suppressive role. By contrast, AREG exhibited upregulation despite Copy Number variation loss, suggesting additional regulatory influences, such as epigenetic or post‑transcriptional mechanisms. Immune cell infiltration analysis demonstrated distinct associations of AREG with CD8+ T‑cells and CX3CR1 with neutrophils and CD4+ T‑cells, underscoring their role in tumor‑immune interactions. Additionally, elevated DNA integrity ratios and the increased expression of AluY subfamilies were observed in patients with technically unresectable OSCC, suggesting a link between transposable element activity and tumor aggressiveness. Molecular docking and dynamics simulations further identified vinorelbine with high binding affinity for AREG, indicating its potential as therapeutic agents against OSCC. Taken together, these findings provide novel insight into the molecular landscape of OSCC and highlight AREG, CX3CR1 and Alu elements as promising biomarkers for diagnosis and prognosis, as well as targets for future therapeutic interventions.
View Figures

Figure 1

Heatmap analysis of genes affecting
both overall survival and disease-free survival in oral cancer.
OSCC, oral squamous cell carcinoma.

Figure 2

Receiver operating characteristic
analysis of upregulated genes affecting both overall survival and
disease-free survival in oral cancer. AUC, area under the
curve.

Figure 3

Receiver operating characteristic
analysis of downregulated genes affecting both overall survival and
disease-free survival in oral cancer. AUC, area under the
curve.

Figure 4

Receiver operating characteristic
analysis of ALDH3A1, HPRT1, AREG, NTRK2, and CX3CR1 genes in
relation to tumor stages in oral cancer.

Figure 5

Association of AREG methylation on
survival outcomes in oral cancer.

Figure 6

Association of CX3CR1 methylation on
survival outcomes in oral cancer.

Figure 7

Spearman's correlation analysis of
(A) AREG and (B) CX3CR1 gene expression and copy number
alterations.

Figure 8

Correlation analysis of (A) AREG and
(B) CX3CR1 expression and immune infiltration.
*P<0.05; NS, not significant (P>0.05).

Figure 9

Expression levels of AREG in the
controls, and in patients with resectable and technically
unresectable oral cancer. Data are presented as the mean ± SEM.

Figure 10

Molecular dynamics simulation
demonstrating (A) RMSD, (B) RMSF, and (C) radius of gyration of
vinorelbine - AREG complex. (D) RMSD, (E) RMSF, and (F) radius of
gyration of AREG- (25s)-neospirost-4-en-3-one. RMSD, root mean
square deviation; RMSF, root mean square fluctuation.

Figure 11

Comparison of Alu concentration in
patients with resectable and technically unresectable oral cancer.
Data are presented as the mean ± SEM. Statistical comparisons
between the two groups were performed using an unpaired two-tailed
Student's t-test. *P<0.05, vs. OSCC. OSCC, oral
squamous cell carcinoma.
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Copy and paste a formatted citation
Spandidos Publications style
Kumari N, Jyotishi C, Patel M and Gupta R: Dual faces of AREG in OSCC: Reduced circulating levels and enhanced tumor expression suggest compartmentalized regulation. World Acad Sci J 8: 6, 2026.
APA
Kumari, N., Jyotishi, C., Patel, M., & Gupta, R. (2026). Dual faces of AREG in OSCC: Reduced circulating levels and enhanced tumor expression suggest compartmentalized regulation. World Academy of Sciences Journal, 8, 6. https://doi.org/10.3892/wasj.2025.421
MLA
Kumari, N., Jyotishi, C., Patel, M., Gupta, R."Dual faces of AREG in OSCC: Reduced circulating levels and enhanced tumor expression suggest compartmentalized regulation". World Academy of Sciences Journal 8.1 (2026): 6.
Chicago
Kumari, N., Jyotishi, C., Patel, M., Gupta, R."Dual faces of AREG in OSCC: Reduced circulating levels and enhanced tumor expression suggest compartmentalized regulation". World Academy of Sciences Journal 8, no. 1 (2026): 6. https://doi.org/10.3892/wasj.2025.421
Copy and paste a formatted citation
x
Spandidos Publications style
Kumari N, Jyotishi C, Patel M and Gupta R: Dual faces of AREG in OSCC: Reduced circulating levels and enhanced tumor expression suggest compartmentalized regulation. World Acad Sci J 8: 6, 2026.
APA
Kumari, N., Jyotishi, C., Patel, M., & Gupta, R. (2026). Dual faces of AREG in OSCC: Reduced circulating levels and enhanced tumor expression suggest compartmentalized regulation. World Academy of Sciences Journal, 8, 6. https://doi.org/10.3892/wasj.2025.421
MLA
Kumari, N., Jyotishi, C., Patel, M., Gupta, R."Dual faces of AREG in OSCC: Reduced circulating levels and enhanced tumor expression suggest compartmentalized regulation". World Academy of Sciences Journal 8.1 (2026): 6.
Chicago
Kumari, N., Jyotishi, C., Patel, M., Gupta, R."Dual faces of AREG in OSCC: Reduced circulating levels and enhanced tumor expression suggest compartmentalized regulation". World Academy of Sciences Journal 8, no. 1 (2026): 6. https://doi.org/10.3892/wasj.2025.421
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