Salivary tumour necrosis factor-alpha and receptor for advanced glycation end products as prognostic and predictive markers for recurrence in oral squamous cell carcinoma – a pilot study
DOI:
https://doi.org/10.15584/ejcem.2023.1.5Keywords:
biomarker, oral squamous cell carcinoma, prognosis, RAGE, saliva, TNF-αAbstract
Introduction and aim. Tumour necrosis factor-alpha (TNF-α) belongs to the cytokine family TNF/TNFR. As a multifunctional cytokine, TNF-α plays a significant role in diverse and a variety of cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory cytokine, TNF-α acts as a bridge between inflammation and carcinogenesis. Receptor for advanced glycation end products (RAGE) are cellular receptors belonging to the immunoglobulin superfamily. As one of the primary mediators of innate immunity, acute and chronic inflammatory disorders, and certain cancers, RAGE signaling plays an important role. The aim of the present study is to analyze the prognostic significance of salivary TNF-α and RAGE in oral squamous cell carcinoma.
Material and methods. A study was conducted testing saliva samples collected from ten patients with well-differentiated and moderately differentiated oral squamous cell carcinomas. To determine the levels of TNF-α and RAGE in unstimulated saliva from patients, an ELISA kit from RAY BIOTECH was used for the study, and the readings were read at 450 nm. Statistical analysis was performed using SPSS software. Version 23 of SPSS was used to plot the standard curve. Statistical comparisons were done using Mann-Whitney U test and ROC analysis.
Results. Salivary TNF-α and RAGE in patients were considered to be induced by radiotherapy at a higher level in moderately differentiated squamous cell carcinoma when compared to well differentiated squamous cell carcinoma. Thus, there is an increase in the induced Salivary TNF-α and RAGE levels by radiotherapy with increase in the histological stages of oral squamous cell carcinoma. The statistical analysis also proved the same.
Conclusion. Hence salivary TNF-α and RAGE may be used as a biomarker for oral cancer to predict the prognosis.
Downloads
References
Obata K, Yutori H, Yoshida K, Sakamoto Y, Ono K, Ibaragi S. Relationships between squamous cell carcinoma antigen and cytokeratin 19 fragment values and renal function in oral cancer patients. Int J Oral Maxillofac Surg. 2022;S0901-5027(22)00353-00358. doi: 10.1016/j.ijom.2022.08.019.
Meng Q, Wu F, Li G, et al. Exploring precise medication strategies for OSCC based on single-cell transcriptome analysis from a dynamic perspective. Cancers (Basel). 2022;14(19):4801. doi: 10.3390/cancers14194801.
Yuan Y, Sturgis EM, Zhu L, et al. A functional variant at the miRNA binding site inE2F1gene is associated with risk and tumor HPV16 status of oropharynx squamous cell carcinoma. Mol Carcinog. 2017;56(3):1100–1106. doi:10.1002/mc.22576
Nijakowski K, Gruszczyński D, Kopała D, Surdacka A. Salivary metabolomics for oral squamous cell carcinoma diagnosis: A systematic review. Metabolites. 2022;12(4):294. doi: 10.3390/metabo12040294.
Hyvärinen E, Savolainen M, Mikkonen JJW, Kullaa AM. Salivary metabolomics for diagnosis and monitoring diseases: Challenges and possibilities. Metabolites. 2021;11(9):587.doi:10.3390/metabo11090587
Hynne H, Sandås EM, Elgstøen KBP, et al. Saliva metabolomics in dry mouth patients with head and neck cancer or Sjögren’s syndrome. Cells. 2022;11(3):323. doi:10.3390/cells11030323
Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA. The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest . 1996; 15,97(4):1111–1116. doi:10.1172/JCI118504
Josephs SF, Ichim TE, Prince SM, Kesari S. Unleashing endogenous TNF-alpha as a cancer immunotherapeutic. J Transl Med. 2018;doi:10.1186/s12967-018-1611-7
Brinkman BM, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL. Relevance of the tumor necrosis factor alpha (TNF alpha) -308 promoter polymorphism in TNF alpha gene regulation. J Inflamm. 1995;46(1):32–41. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8832970
Bessaleli E, Scheinfeld N, Kroumpouzos- G. Squamous cell carcinoma of the cervix arising in a patient on adalimumab-a need for cervical screenings in patients on tumor necrosis factor inhibitors. Dermatol Online J. 2018;24(5). Available from: https://www.ncbi.nlm.nih.gov/pubmed/30142745
Zielińska K, Karczmarek-Borowska B, Kwaśniak K, et al. Salivary IL-17A, IL-17F, and TNF- Are Associated with Disease Advancement in Patients with Oral and Oropharyngeal Cancer. J Immunol Res. 2020;2020:3928504.doi:10.1155/2020/3928504
Sethi G, Sung B, Aggarwal BB. TNF: a master switch for inflammation to cancer. Front Biosci. 2008;13:5094–5107. doi:10.2741/3066
Cunha FQ, Poole S, Lorenzetti BB, Ferreira SH. The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia. Br J Pharmacol. 1992;107(3):660–664. doi:10.1111/j.1476-5381.1992.tb14503.x
ThamaraiSelvi VT, Brundha MP. Salivaomics-A Review. European Journal of Molecular & Clinical Medicine. 2020;7(1):2914–2931. Available from: https://www.ejmcm.com/article_3336_7e4099c5dddc87a6bd92447a5c3cbf5e.pdf
Rithanya M, Brundha MP. Molecular immune pathogenesis and diagnosis of COVID-19 - A review. Int J Curr Res Rev. 2020;69–73. Available from: https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-1011906
Wang Y, Yang J, Huang J, Tian Z. Tumor Necrosis Factor-α Polymorphisms and Cervical Cancer: Evidence from a Meta-Analysis. Gynecol Obstet Invest. 2020;85(2):153–158. doi:10.1159/000502955
Hofmann MA, Drury S, Fu C, et al. RAGE Mediates a Novel Proinflammatory Axis: A Central Cell Surface Receptor for S100/Calgranulin Polypeptides. Cell. 1999;97(7):889–901. Available from: https://www.cell.com/cell/abstract/S0092-8674(00)80801-6
Tian J, Avalos AM, Mao SY, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8(5):487–496. doi:10.1038/ni1457
Orlova VV, Choi EY, Xie C, et al. A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J. 2007;26(4):1129–1139. doi:10.1038/sj.emboj.7601552
Taguchi A, Blood DC, del Toro G, et al. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature. 2000;405(6784):354–360. doi:10.1038/35012626
Ishihara K, Tsutsumi K, Kawane S, Nakajima M, Kasaoka T. The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site. FEBS Lett. 2003 ;550(1–3):107–113. doi:10.1016/s0014-5793(03)00846-9
Syed DN, Aljohani A, Waseem D, Mukhtar H. Ousting RAGE in melanoma: a viable therapeutic target? Semin Cancer Biol. 2018;49:20–28. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910174/
Chiamulera MMA, Zancan CB, Remor AP, Cordeiro MF, Gleber-Netto FO, Baptistella AR. Salivary cytokines as biomarkers of oral cancer: a systematic review and meta-analysis. BMC Cancer. 2021;21(1):205.doi:10.1186/s12885-021-07932-3
Gupta DS, Gupta S, Gupta O, Chandra S. Genetic polymorphism of tumor necrosis factor alpha (TNF-Α) and tumor necrosis factor beta (TNF-Β) genes and risk of oral pre cancer and cancer. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2019;128(1) p. e88.doi:10.1016/j.oooo.2019.02.224
Agnihotri SK, Kumar B, Jain A, et al. Clinical significance of circulating serum levels of sCD95 and TNF-α in cytoprotection of cervical cancer. Rep Biochem Mol Biol. 2022;10(4):711–721. doi:10.52547/rbmb.10.4.711
Khurshid Z, Zafar MS, Khan RS, Najeeb S, Slowey PD, Rehman IU. Role of Salivary Biomarkers in Oral Cancer Detection. Adv Clin Chem. 2018;86:23–70. doi:10.1016/bs.acc.2018.05.002
Rao E, Hou Y, Huang X, et al. All-trans retinoic acid overcomes solid tumor radioresistance by inducing inflammatory macrophages. Sci Immunol. 2021;6(60). doi:10.1126/sciimmunol.aba8426
Bossi P, Bergamini C, Miceli R, et al. Salivary Cytokine Levels and Oral Mucositis in Head and Neck Cancer Patients Treated With Chemotherapy and Radiation Therapy. Int J Radiat Oncol Biol Phys. 2016;96(5):959–966. doi:10.1016/j.ijrobp.2016.08.047
Harsha L, Brundha MP. Prevalence of Dental Developmental Anomalies among Men and Women and its Psychological Effect in a Given Population. Journal of Pharmaceutical Sciences and Research; Cuddalore. 2017;9(6):869–873. Available from: https://www.proquest.com/scholarly-journals/prevalence-dental-developmental-anomalies-among/docview/1917938864/se-2
Timothy CN, Samyuktha PS, Brundha MP. Dental pulp Stem Cells in Regenerative Medicine-A Literature Review. Research Journal of Pharmacy and Technology. 2019;12(8):4052–4056. Available from: https://www.indianjournals.com/ijor.aspx?target=ijor:rjpt&volume=12&issue=8&article=088
Oton-Leite AF, Silva GBL, Morais MO, et al. Effect of low-level laser therapy on chemoradiotherapy-induced oral mucositis and salivary inflammatory mediators in head and neck cancer patients. Lasers Surg Med. 2015;47(4):296–305. doi:10.1002/lsm.22349
G D, Nandan SRK, Kulkarni PG. Salivary Tumour Necrosis Factor-α as a Biomarker in Oral Leukoplakia and Oral Squamous Cell Carcinoma. Asian Pac J Cancer Prev. 2019;20(7):2087–2093. doi:10.31557/APJCP.2019.20.7.2087
Krishnan R, Thayalan DK, Padmanaban R, Ramadas R, Annasamy RK, Anandan N. Association of serum and salivary tumor necrosis factor-α with histological grading in oral cancer and its role in differentiating premalignant and malignant oral disease. Asian Pac J Cancer Prev. 2014;15(17):7141–7148. doi:10.7314/apjcp.2014.15.17.7141
Nankali M, Karimi J, Goodarzi MT, et al. Increased Expression of the Receptor for Advanced Glycation End-Products (RAGE) Is Associated with Advanced Breast Cancer Stage. Oncol Res Treat. 2016;39(10):622–628. doi:10.1159/000449326
Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ. HMGB1 and RAGE in Inflammation and Cancer, Annual Review of Immunology. 2010;28(2):367–388. doi:10.1146/annurev.immunol.021908.132603
Bhawal UK, Ozaki Y, Nishimura M, et al. Association of Expression of Receptor for Advanced Glycation End Products and Invasive Activity of Oral Squamous Cell Carcinoma. Oncology. 2005;69(3)255. doi:10.1159/000087910 Abe R, Yamagishi SI. AGE-RAGE system and carcinogenesis. Curr Pharm Des. 2008;14(10):940–945. doi:10.2174/138161208784139765
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 European Journal of Clinical and Experimental Medicine

This work is licensed under a Creative Commons Attribution 4.0 International License.
Our open access policy is in accordance with the Budapest Open Access Initiative (BOAI) definition: this means that articles have free availability on the public Internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from having access to the Internet itself.
All articles are published with free open access under the CC-BY Creative Commons attribution license (the current version is CC-BY, version 4.0). If you submit your paper for publication by the Eur J Clin Exp Med, you agree to have the CC-BY license applied to your work. Under this Open Access license, you, as the author, agree that anyone may download and read the paper for free. In addition, the article may be reused and quoted provided that the original published version is cited. This facilitates freedom in re-use and also ensures that Eur J Clin Exp Med content can be mined without barriers for the research needs.




