Journal of Kerman University of Medical Sciences

Current Issue

By Issue

By Author

Author Index

Keyword Index

About Journal

Aims and Scope

JKMU Ethical Policies

Indexing and Abstracting

Related Links

FAQ

Peer Review Process

News

Metric

Assessment of Serum Interleukin-38 Levels in Iranian Patients with Benign and Malignant Salivary Gland Cancers: A Case-Control Study

Document Type : Original Article

Authors

1 Department of Surgery, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran

3 Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

4 Department of Oral and Maxillofacial Medicine, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran

5 Oral and Dental Disease Research Center, Department of Oral and Maxillofacial Medicine, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

Background: Similar to other cancers, the development of salivary gland cancers (SGCs) is influenced by the tumor microenvironment and controlled by the host's immune system. Interleukin-38 (IL-38) is highly expressed in inflammatory conditions to prevent excessive inflammatory responses and tissue injury; however, its role in SGCs remains unclear. This study aimed to evaluate IL-38 serum levels in Iranian patients with benign and malignant SGCs and in healthy individuals to explore its potential as a diagnostic biomarker for SGCs.
Methods: In this retrospective cross-sectional study, IL-38 levels were measured in serum samples from 120 patients with SGCs (64 benign and 56 malignant cases) and 60 age- and sex-matched healthy control participants using a sandwich enzyme-linked immunosorbent assay (ELISA) kit.
Results: There was a significant difference in IL-38 serum levels between patients and the control group (49.1 ± 6.2 ng/L vs. 38.6 ± 6.8 ng/L, p < 0.0001), but not between benign and malignant cases (48.2 ± 7.1 ng/L vs. 50.2 ± 4.8 ng/L, p = 0.085). A significant negative correlation was observed between SGC size and IL-38 serum levels (R = −0.195, p = 0.042). However, IL-38 was not associated with other clinicopathologic factors, including gender, age, tumor type, lesion location, and tumor stage (p > 0.05).
Conclusion: This study, for the first time, supports the clinical value of IL-38 serum levels as a valuable biomarker for diagnosing patients with SGCs. Focusing on IL-38 production or its release mechanism could offer therapeutic benefits for these patients. However, further research with a larger sample is required.

Highlights

Ali Tadayon (Google Scholar) (PubMed)

Javad Moayedi (Google Scholar) (PubMed)

Mohammad Javad Fattahi (Google Scholar) (PubMed)

Behnaz Nazari (Google Scholar) (PubMed)

Maryam Mardani (Google Scholar) (PubMed)

Keywords

Main Subjects

References
  1. Porcheri C, Mitsiadis TA. Physiology, pathology and regeneration of salivary glands. Cells. 2019;8(9):976-95. doi: 10.3390/cells8090976.
  2. Krishnamurthy S, Vasudeva SB, Vijayasarathy S. Salivary gland disorders: A comprehensive review. World Journal of Stomatology. 2015;4(2):56-71. doi: 10.5321/wjs.v4.i2.56.
  3. Mandel L. Salivary gland disorders. Medical Clinics. 2014;98(6):1407-49. doi: 10.1016/j.mcna.2014.08.008.
  4. Mardani M, Andisheh-Tadbir A, Pourshahian S, Khademi B, Malekzadeh M. Evaluation of the serum level of high mobility group box 1 protein in benign and malignant salivary gland tumors. Acta Medica Iranica. 2021;59(9):530-5. doi: 10.18502/acta.v59i9.7553.
  5. Shahsavari F, Khaniki M, Farbod M. Prevalence of Salivary Glands Lesions in Iran: A 10-Year Retrospective Study. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2015;119(3):e174. doi: 10.1016/j.oooo.2014.07.319.
  6. Taghavi N, Sargolzaei S, Mashhadiabbas F, Akbarzadeh A, Kardouni P. Salivary gland tumors: a 15-year report from Iran. Turkish Journal of Pathology. 2016;32(1):35-9. doi: 10.5146/tjpath.2015.01336.
  7. Bello IO, Salo T, Dayan D, Tervahauta E, Almangoush A, Schnaiderman-Shapiro A, et al. Epithelial salivary gland tumors in two distant geographical locations, Finland (Helsinki and Oulu) and Israel (Tel Aviv): a 10-year retrospective comparative study of 2,218 cases. Head and Neck Pathology. 2012;6(2):224-31. doi: 10.1007/s12105-011-0316-5.
  8. Żurek M, Rzepakowska A, Jasak K, Niemczyk K. The Epidemiology of Salivary Glands Pathologies in Adult Population over 10 Years in Poland—Cohort Study. International Journal of Environmental Research and Public Health. 2021;19(1):179-89. doi: 10.3390/ijerph19010179.
  9. Cunha JLS, Hernandez-Guerrero JC, de Almeida OP, Soares CD, Mosqueda-Taylor A. Salivary gland tumors: a retrospective study of 164 cases from a single private practice service in Mexico and literature review. Head and Neck Pathology. 2021;15(2):523-31. doi: 10.1007/s12105-020-01231-2.
  10. Fonseca FP, de Vasconcelos Carvalho M, de Almeida OP, Rangel ALCA, Takizawa MCH, Bueno AG, Vargas PA. Clinicopathologic analysis of 493 cases of salivary gland tumors in a Southern Brazilian population. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2012;114(2):230-9. doi: 10.1016/j.oooo.2012.04.008.
  11. Pan SY, de Groh M, Morrison H. A case-control study of risk factors for salivary gland cancer in Canada. Journal of Cancer Epidemiology. 2017;2017(4909214):1-12. doi: 10.1155/2017/4909214.
  12. Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB. Inflammation and cancer. Annals of African Medicine. 2019;18(3):121-6. doi: 10.4103/aam.aam_56_18.
  13. Wu B, Sodji QH, Oyelere AK. Inflammation, fibrosis and cancer: Mechanisms, therapeutic options and challenges. Cancers. 2022;14(3):552-89. doi: 10.3390/cancers14030552.
  14. Diaz-Barreiro A, Huard A, Palmer G. Multifaceted roles of IL-38 in inflammation and cancer. Cytokine. 2022;151(155808):1-15. doi: 10.1016/j.cyto.2022.155808.
  15. Fazeli P, Saeidnia M, Erfani M, Kalani M. An overview of the biological and multifunctional roles of IL-38 in different infectious diseases and COVID-19. Immunologic Research. 2022;70(1):316-24. doi: 10.1007/s12026-022-09275-y.
  16. Dang J, He Z, Cui X, Fan J, Hambly DJ, Hambly BD, et al. The role of IL-37 and IL-38 in colorectal cancer. Frontiers in Medicine. 2022;9(811025):1-7. doi: 10.3389/fmed.2022.811025.
  17. Wang F, Zhang W, Wu T, Chu H. Reduced interleukin-38 in non-small cell lung cancer is associated with tumour progression. Open Biology. 2018;8(10):180132-42. doi: 10.1098/rsob.180132.
  18. Kinoshita F, Tagawa T, Akamine T, Takada K, Yamada Y, Oku Y, et al. Interleukin-38 promotes tumor growth through regulation of CD8+ tumor-infiltrating lymphocytes in lung cancer tumor microenvironment. Cancer Immunology, Immunotherapy. 2021;70(1):123-35. doi: 10.1007/s00262-020-02659-9.
  19. Huang L, Zhang H, Zhao D, Hu H, Lu Z. Interleukin-38 Suppresses Cell Migration and Proliferation and Promotes Apoptosis of Colorectal Cancer Cell Through Negatively Regulating Extracellular Signal-Regulated Kinases Signaling. Journal of Interferon and Cytokine Research. 2021;41(10):375-84. doi: 10.1089/jir.2021.0047.
  20. Takada K, Okamoto T, Tominaga M, Teraishi K, Akamine T, Takamori S, et al. Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression. PLoS One. 2017;12(7):e0181598. doi: 10.1371/journal.pone.0181598.
  21. van de Veerdonk FL, Stoeckman AK, Wu G, Boeckermann AN, Azam T, Netea MG, et al. IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist. Proceedings of the National Academy of Sciences. 2012;109(8):3001-5. doi: 10.1073/pnas.1121534109.
  22. Yuan X, Peng X, Li Y, Li M. Role of IL-38 and its related cytokines in inflammation. Mediators of Inflammation. 2015;2015(807976):1-7. doi: 10.1155/2015/807976.
  23. Lavareze L, Scarini JF, de Lima-Souza RA, Emerick C, de Sá RS, Aquino IG, et al. Salivary gland cancer in the setting of tumor microenvironment: Translational routes for therapy. Critical Reviews in Oncology/Hematology. 2022;171(103605):1-10. doi: 10.1016/j.critrevonc.2022.103605.
  24. Egal ESA, Scarini JF, de Lima-Souza RA, Lavareze L, Fernandes PM, Emerick C, et al. Tumor microenvironment in salivary gland carcinomas: An orchestrated state of chaos. Oral Oncology. 2022;127(105777):1-11. doi: 10.1016/j.oraloncology.2022.105777.
  25. Garraud T, Harel M, Boutet M-A, Le Goff B, Blanchard F. The enigmatic role of IL-38 in inflammatory diseases. Cytokine and Growth Factor Reviews. 2018;39(1):26-35. doi: 10.1016/j.cytogfr.2018.01.001.
  26. Esmaeilzadeh A, Bahmaie N, Nouri E, Hajkazemi MJ, Zareh Rafie M. Immunobiological Properties and Clinical Applications of Interleukin-38 for Immune-Mediated Disorders: A Systematic Review Study. International Journal of Molecular Sciences. 2021;22(22):12552-86. doi: 10.3390/ijms222212552.
  27. de Graaf DM, Teufel LU, Joosten LA, Dinarello CA. Interleukin-38 in health and disease. Cytokine. 2022;152:155824. doi: 10.1016/j.cyto.2022.155824.
  28. Da Silva P, Mora J, You X, Wiechmann S, Putyrski M, Garcia-Pardo J, et al. Neutralizing IL-38 activates γδ T cell-dependent antitumor immunity and sensitizes for chemotherapy. Journal for ImmunoTherapy of Cancer. 2024;12(8):e008641. doi: 10.1136/jitc-2023-008641.
  29. Jarnicki AG, Lysaght J, Todryk S, Mills KH. Suppression of antitumor immunity by IL-10 and TGF-β-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. The Journal of Immunology. 2006;177(2):896-904. doi: 10.4049/jimmunol.177.2.896.
  30. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.
  31. Dowling JP, Nikitin PA, Shen F, Shukla H, Finn JP, Patel N, et al. IL-38 blockade induces anti-tumor immunity by abrogating tumor-mediated suppression of early immune activation. MAbs. 2023;15(1):2212673. doi: 10.1080/19420862.2023.2212673.
  32. Finucane M, Brint E, Houston A. The complex roles of IL-36 and IL-38 in cancer: friends or foes? Oncogene. 2025:1-11. doi: 10.1038/s41388-025-03293-4.
  33. Grivennikov SI, Karin M. Inflammation and oncogenesis: a vicious connection. Current Opinion in Genetics & Development. 2010;20(1):65-71. doi: 10.1016/j.gde.2009.11.004.
  34. Darai E, Detchev R, Hugol D, Quang NT. Serum and cyst fluid levels of interleukin (IL)‐6, IL‐8 and tumour necrosis factor‐alpha in women with endometriomas and benign and malignant cystic ovarian tumours. Human Reproduction. 2003;18(8):1681-5. doi: 10.1093/humrep/deg321.
  35. Zhu K, Shi J, Yang R, Zhou C, Liu Z. Identification of cytokines in benign and malignant thymus tumors: based on Mendelian randomization and proteomics. Frontiers in Endocrinology. 2024;15:1390140. doi: 10.3389/fendo.2024.1390140.
  36. Abdul-Rahman T, Ghosh S, Badar SM, Nazir A, Bamigbade GB, Aji N, et al. The paradoxical role of cytokines and chemokines at the tumor microenvironment: a comprehensive review. European Journal of Medical Research. 2024;29(124):1-19. doi: 0.1186/s40001-024-01711-z.
  37. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. Journal of immunology research. 2014;2014(1):149185. doi: 10.1155/2014/149185.
  38. Wang X, Luo Y, Li M, Yan H, Sun M, Fan T. Management of salivary gland carcinomas-a review. Oncotarget. 2017;8(3):3946-56. doi: 10.18632/oncotarget.13952.
  39. Peravali RK, Bhat HHK, Upadya VH, Agarwal A, Naag S. Salivary gland tumors: a diagnostic dilemma! Journal of Maxillofacial and Oral Surgery. 2015;14(1):438-42. doi: 10.1007/s12663-014-0665-1.
  40. Barak V, Meirovitz A, Leibovici V, Rachmut J, Peretz T, Eliashar R, Gross M. The diagnostic and prognostic value of tumor markers (CEA, SCC, CYFRA 21-1, TPS) in head and neck cancer patients. Anticancer Research. 2015;35(10):5519-24. doi.
  41. Yuan C, Yang K, Tang H, Chen D. Diagnostic values of serum tumor markers Cyfra21-1, SCCAg, ferritin, CEA, CA19-9, and AFP in oral/oropharyngeal squamous cell carcinoma. OncoTargets and Therapy. 2016;9(1):3381-6. doi: 10.2147/OTT.S105672.
  42. Chung HW, Lee S-G, Kim H, Hong DJ, Chung JB, Stroncek D, Lim J-B. Serum high mobility group box-1 (HMGB1) is closely associated with the clinical and pathologic features of gastric cancer. Journal of Translational Medicine. 2009;7(1):1-11. doi: 10.1186/1479-5876-7-38.
  43. Chen F, Zhang F, Tan Z, Hambly BD, Bao S, Tao K. Interleukin-38 in colorectal cancer: a potential role in precision medicine. Cancer Immunology, Immunotherapy. 2020;69(1):69-79. doi: 10.1007/s00262-019-02440-7.
  44. Baker KJ, Houston A, Brint E. IL-1 family members in cancer; two sides to every story. Frontiers in Immunology. 2019;10(1):1197-213. doi: 10.3389/fimmu.2019.01197.
Journal of Kerman University of Medical Sciences
Volume 33
Pages 1-7
Files
Share
How to cite
Statistics