BACKGROUND: The incidence of squamous cell carcinoma of the oral tongue (SCCOT) among young adults is increasing in several regions of the world. Age-dependent differences in the biology of SCCOT have been suspected. METHODS: We used the Olink Explore 3072 high-throughput platform to comprehensively quantify plasma proteins in 24 young (≤ 40 years of age) and 50 old (> 50 years of age) individuals. Eight young and 20 old individuals were diagnosed with SCCOT, four young and nine old individuals with SCC at other oral subsites (SCCOO), and the remaining 12 young and 21 old individuals were healthy controls. Dimension reduction analysis, differential expression analysis, and functional enrichment analysis were performed to characterize young patient-specific biological signatures. RESULTS: Plasma levels of 2923 proteins were obtained. Principal component analysis indicated age-related expression patterns. Comparing young patients to young controls/old patients/old controls, differential abundance analysis showed that increases in protein levels of Peroxiredoxin 2 (PRDX2) and C-C motif chemokine ligand 26 (CCL26) and a decrease in Kallikrein related peptidase 4 (KLK4) were young patient-specific. Reactome pathway enrichment analysis identified "Cellular response to chemical stress," "Detoxification of reactive oxygen species" and "Cellular responses to stimuli" as the top altered pathways in young patients with SCCOT. CONCLUSIONS: Abnormal cellular stress and aberrant immune regulation could thus be linked to cancer development in young patients. The unique plasma proteomic signature observed in young patients with SCCOT suggests that they constitute a specific group with distinct underlying pathophysiological processes.

Department of Clinical Sciences ENT Umeå University Umeå Sweden

Department of Medical Biosciences Pathology Umeå University Umeå Sweden

Department of Oral and Maxillo Facial Surgery Mater Dei Hospital Bari Italy

Research Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Zobrazit více v PubMed

Sung H., Ferlay J., Siegel R. L., et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 71, no. 3 (2021): 209–249. PubMed

Johnson D. E., Burtness B., Leemans C. R., Lui V. W. Y., Bauman J. E., and Grandis J. R., “Head and Neck Squamous Cell Carcinoma,” Nature Reviews. Disease Primers 6, no. 1 (2020): 92. PubMed PMC

Farhood Z., Simpson M., Ward G. M., Walker R. J., and Osazuwa‐Peters N., “Does Anatomic Subsite Influence Oral Cavity Cancer Mortality?,” A SEER Database Analysis. Laryngoscope 129, no. 6 (2019): 1400–1406. PubMed

Kim Y. J. and Kim J. H., “Increasing Incidence and Improving Survival of Oral Tongue Squamous Cell Carcinoma,” Scientific Reports 10, no. 1 (2020): 7877. PubMed PMC

Deneuve S., Perol O., Dantony E., et al., “Diverging Incidence Trends of Oral Tongue Cancer Compared to Other Head and Neck Cancers in Young Adults in France,” International Journal of Cancer 150, no. 8 (2022): 1301–1309. PubMed

Ng J. H., Iyer N. G., Tan M. H., and Edgren G., “Changing Epidemiology of Oral Squamous Cell Carcinoma of the Tongue: A Global Study,” Head & Neck 39, no. 2 (2017): 297–304. PubMed

Williams S. A., Kivimaki M., Langenberg C., et al., “Plasma Protein Patterns as Comprehensive Indicators of Health,” Nature Medicine 25, no. 12 (2019): 1851–1857. PubMed PMC

Emilsson V., Ilkov M., Lamb J. R., et al., “Co‐Regulatory Networks of Human Serum Proteins Link Genetics to Disease,” Science 361, no. 6404 (2018): 769–773. PubMed PMC

Lehallier B., Gate D., Schaum N., et al., “Undulating Changes in Human Plasma Proteome Profiles Across the Lifespan,” Nature Medicine 25, no. 12 (2019): 1843–1850. PubMed PMC

Kolberg L., Raudvere U., Kuzmin I., Adler P., Vilo J., and Peterson H., “G:Profiler‐Interoperable Web Service for Functional Enrichment Analysis and Gene Identifier Mapping (2023 Update),” Nucleic Acids Research 51, no. W1 (2023): W207–W212. PubMed PMC

Subramanian A., Tamayo P., Mootha V. K., et al., “Gene Set Enrichment Analysis: A Knowledge‐Based Approach for Interpreting Genome‐Wide Expression Profiles,” Proceedings of the National Academy of Sciences of the United States of America 102, no. 43 (2005): 15545–15550. PubMed PMC

Barbie D. A., Tamayo P., Boehm J. S., et al., “Systematic RNA Interference Reveals That Oncogenic KRAS‐Driven Cancers Require TBK1,” Nature 462, no. 7269 (2009): 108–112. PubMed PMC

Reich M., Liefeld T., Gould J., Lerner J., Tamayo P., and Mesirov J. P., “GenePattern 2.0,” Nature Genetics 38, no. 5 (2006): 500–501. PubMed

Harada H., Kikuchi M., Asato R., et al., “Characteristics of Oral Squamous Cell Carcinoma Focusing on Cases Unaffected by Smoking and Drinking: A Multicenter Retrospective Study,” Head & Neck 45, no. 7 (2023): 1812–1822. PubMed

Bello I. O., Almangush A., Heikkinen I., et al., “Histological Characteristics of Early‐Stage Oral Tongue Cancer in Young Versus Older Patients: A Multicenter Matched‐Pair Analysis,” Oral Diseases 26, no. 5 (2020): 1081–1085. PubMed

Pickering C. R., Zhang J., Neskey D. M., et al., “Squamous Cell Carcinoma of the Oral Tongue in Young Non‐Smokers Is Genomically Similar to Tumors in Older Smokers,” Clinical Cancer Research 20, no. 14 (2014): 3842–3848. PubMed PMC

Gu X., Coates P. J., Boldrup L., et al., “Copy Number Variation: A Prognostic Marker for Young Patients With Squamous Cell Carcinoma of the Oral Tongue,” Journal of Oral Pathology & Medicine 48, no. 1 (2019): 24–30. PubMed PMC

Jones B. M., Villavisanis D. F., Lehrer E. J., et al., “High Failure Rates in Young Nonsmoker Nondrinkers With Squamous Cell Carcinoma of the Oral Tongue,” Laryngoscope 133, no. 5 (2023): 1110–1121. PubMed

Baba D., Matsuura K., Wakabayashi M., et al., “Comparison Between Three Age‐Stratified Cohorts Reveals Poor Prognosis of Young Patients With Tongue Carcinoma,” Frontiers in Oncology 12 (2022): 959749. PubMed PMC

Omura G., Yoshimoto S., Rikitake R., Eguchi K., Nakamizo M., and Nibu K. I., “Comparison of Survival Outcomes Between Adolescent and Young Adults and Older Adults With Tongue Squamous Cell Carcinoma: A Nationwide Database Study Using the Head and Neck Cancer Registry of Japan,” International Journal of Clinical Oncology 28, no. 2 (2023): 221–228. PubMed

Tagliabue M., Belloni P., De Berardinis R., et al., “A Systematic Review and Meta‐Analysis of the Prognostic Role of Age in Oral Tongue Cancer,” Cancer Medicine 10, no. 8 (2021): 2566–2578. PubMed PMC

Kim S. H., Monticone R. E., McGraw K. R., and Wang M., “Age‐Associated Proinflammatory Elastic Fiber Remodeling in Large Arteries,” Mechanisms of Ageing and Development 196 (2021): 111490. PubMed PMC

Karas A., Holmannova D., Borsky P., et al., “Significantly Altered Serum Levels of NAD, AGE, RAGE, CRP, and Elastin as Potential Biomarkers of Psoriasis and Aging‐A Case‐Control Study,” Biomedicine 10, no. 5 (2022): 1133. PubMed PMC

Bao L., Shi V. Y., and Chan L. S., “IL‐4 Regulates Chemokine CCL26 in Keratinocytes Through the Jak1, 2/Stat6 Signal Transduction Pathway: Implication for Atopic Dermatitis,” Molecular Immunology 50, no. 1–2 (2012): 91–97. PubMed

Lan Q., Lai W., Zeng Y., et al., “CCL26 Participates in the PRL‐3‐Induced Promotion of Colorectal Cancer Invasion by Stimulating Tumor‐Associated Macrophage Infiltration,” Molecular Cancer Therapeutics 17, no. 1 (2018): 276–289. PubMed

Sun A., Li Y., and Jiang X., “CCL26 Silence Represses Colon Cancer by Inhibiting the EMT Signaling Pathway,” Tissue & Cell 79 (2022): 101937. PubMed

Domaingo A., Jokesch P., Schweiger A., et al., “Chemokine Binding to Tenascin‐C Influences Chemokine‐Induced Immune Cell Migration,” International Journal of Molecular Sciences 24, no. 19 (2023): 14694. PubMed PMC

Liu L., Guan S., Xue Y., et al., “The Immunological Landscape of CCL26(High) Invasive Oral Squamous Cell Carcinoma,” Frontiers in Cell and Development Biology 13 (2025): 1502073. PubMed PMC

Estephan L. E., Kumar G., Stewart M., et al., “Altered Extracellular Matrix Correlates With an Immunosuppressive Tumor Microenvironment and Disease Progression in Younger Adults With Oral Cavity Squamous Cell Carcinoma,” Frontiers in Oncology 14 (2024): 1412212. PubMed PMC

Patysheva M. R., Kolegova E. S., Khozyainova A. A., et al., “Revealing Molecular Mechanisms of Early‐Onset Tongue Cancer by Spatial Transcriptomics,” Scientific Reports 14, no. 1 (2024): 26255. PubMed PMC

Tagirasa R. and Yoo E., “Role of Serine Proteases at the Tumor‐Stroma Interface,” Frontiers in Immunology 13 (2022): 832418. PubMed PMC

Hayes J. D., Dinkova‐Kostova A. T., and Tew K. D., “Oxidative Stress in Cancer,” Cancer Cell 38, no. 2 (2020): 167–197. PubMed PMC

Cheung E. C. and Vousden K. H., “The Role of ROS in Tumour Development and Progression,” Nature Reviews. Cancer 22, no. 5 (2022): 280–297. PubMed

Forman H. J. and Zhang H., “Targeting Oxidative Stress in Disease: Promise and Limitations of Antioxidant Therapy,” Nature Reviews. Drug Discovery 20, no. 9 (2021): 689–709. PubMed PMC

Thomson J., Singh M., Eckersley A., Cain S. A., Sherratt M. J., and Baldock C., “Fibrillin Microfibrils and Elastic Fibre Proteins: Functional Interactions and Extracellular Regulation of Growth Factors,” Seminars in Cell & Developmental Biology 89 (2019): 109–117. PubMed PMC

Heinz A., “Elastic Fibers During Aging and Disease,” Ageing Research Reviews 66 (2021): 101255. PubMed