Iranian Journal of Medical Sciences

Document Type : Original Article(s)


1 Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

2 Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

3 Non-Communicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran

4 Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran



Background: Opium abuse is one of the social hazards in the Middle Eastern countries. Opium consumption attributes to various malignancies. However, the exact molecular mechanism of this correlation still remains unclear. Cancer and inflammation are closely correlated. Interleukin-33 (IL-33) and its receptors, transmembrane ST2 (ST2L) and soluble ST2 (sST2), have been significantly associated with tumorigenicity. The present study aimed to investigate whether IL-33 and sST2 levels serve as cancer biomarkers in opium users.
Methods: Serum samples were collected from 100 opium users and 100 healthy non-opium users in a nested case-control design. The subjects with over five years of history of opium abuse were enrolled. To assess the incidence of malignancies, the opium users were followed up from 2014 to 2019. Serum levels of IL-33 and sST2 were measured using an ELISA kit. For comparison of IL-33 and sST2 levels between the groups, two-tailed Student’s t test and Mann–Whitney U test were utilized, accordingly. Logistic regression analysis was performed to evaluate the influence of confounders on the incidence of cancer.
Results: During the five-year follow-up, eight opium users were diagnosed with cancer. Cancer was developed by 9.3 folds in the individuals abusing opium compared to that in the non-opium users (P=0.040, OR=9.3; 95%CI [1.1-79.4]). Serum levels of IL-33 were found to be significantly higher in the opium users than those in the healthy control group (P=0.001). The sST2 levels were significantly lower in the opium users (P=0.001). The opium users with cancer exhibited significantly higher levels of IL-33 and lower levels of sST2 than the cancer-free ones (P=0.001).
Conclusion: Decline in sST2 levels and rise in the level of IL-33 are valuable biomarkers in predicting cancers. Regarding the significant alterations in the levels of these biomarkers in the opium users, as well as those in the opium users diagnosed with cancer, IL-33 and sST2 may serve as potential biomarkers in the early prediction of cancer.


  1. Amin-Esmaeili M, Rahimi-Movaghar A, Sharifi V, Hajebi A, Radgoodarzi R, Mojtabai R, et al. Epidemiology of illicit drug use disorders in Iran: prevalence, correlates, comorbidity and service utilization results from the Iranian Mental Health Survey. Addiction. 2016;111:1836-47. doi: 10.1111/add.13453. PubMed PMID: 27177849.
  2. Moossavi S, Mohamadnejad M, Pourshams A, Poustchi H, Islami F, Sharafkhah M, et al. Opium Use and Risk of Pancreatic Cancer: A Prospective Cohort Study. Cancer Epidemiol Biomarkers Prev. 2018;27:268-73. doi: 10.1158/1055-9965.EPI-17-0592. PubMed PMID: 29263189; PubMed Central PMCID: PMCPMC5835180.
  3. Kamangar F, Shakeri R, Malekzadeh R, Islami F. Opium use: an emerging risk factor for cancer? Lancet Oncol. 2014;15:e69-77. doi: 10.1016/S1470-2045(13)70550-3. PubMed PMID: 24480557.
  4. Mahmoodpoor A, Golzari SE. Epigenetics, opium, and cancer. Lancet Oncol. 2014;15:e153. doi: 10.1016/S1470-2045(14)70077-4. PubMed PMID: 24694638.
  5. Liang X, Liu R, Chen C, Ji F, Li T. Opioid System Modulates the Immune Function: A Review. Transl Perioper Pain Med. 2016;1:5-13. PubMed PMID: 26985446; PubMed Central PMCID: PMCPMC4790459.
  6. Wang J, Barke RA, Ma J, Charboneau R, Roy S. Opiate abuse, innate immunity, and bacterial infectious diseases. Arch Immunol Ther Exp (Warsz). 2008;56:299-309. doi: 10.1007/s00005-008-0035-0. PubMed PMID: 18836861.
  7. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519-50. doi: 10.1146/annurev.immunol.021908.132612. PubMed PMID: 19302047.
  8. Dinarello CA. Overview of the interleukin-1 family of ligands and receptors. Semin Immunol. 2013;25:389-93. doi: 10.1016/j.smim.2013.10.001. PubMed PMID: 24275600.
  9. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479-90. doi: 10.1016/j.immuni.2005.09.015. PubMed PMID: 16286016.
  10. Mueller T, Jaffe AS. Soluble ST2--analytical considerations. Am J Cardiol. 2015;115:8B-21B. doi: 10.1016/j.amjcard.2015.01.035. PubMed PMID: 25697919.
  11. Bourgeois E, Van LP, Samson M, Diem S, Barra A, Roga S, et al. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production. Eur J Immunol. 2009;39:1046-55. doi: 10.1002/eji.200838575. PubMed PMID: 19266498.
  12. Saluja R, Hawro T, Eberle J, Church MK, Maurer M. Interleukin-33 promotes the proliferation of mouse mast cells through ST2/MyD88 and p38 MAPK-dependent and Kit-independent pathways. J Biol Regul Homeost Agents. 2014;28:575-85. PubMed PMID: 25620169.
  13. Cayrol C, Girard JP. Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. Immunol Rev. 2018;281:154-68. doi: 10.1111/imr.12619. PubMed PMID: 29247993.
  14. Braun H, Afonina IS, Mueller C, Beyaert R. Dichotomous function of IL-33 in health and disease: From biology to clinical implications. Biochem Pharmacol. 2018;148:238-52. doi: 10.1016/j.bcp.2018.01.010. PubMed PMID: 29309756.
  15. Pinto SM, Subbannayya Y, Rex DAB, Raju R, Chatterjee O, Advani J, et al. A network map of IL-33 signaling pathway. J Cell Commun Signal. 2018;12:615-24. doi: 10.1007/s12079-018-0464-4. PubMed PMID: 29705949; PubMed Central PMCID: PMCPMC6039344.
  16. Miller AM, Asquith DL, Hueber AJ, Anderson LA, Holmes WM, McKenzie AN, et al. Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in mice. Circ Res. 2010;107:650-8. doi: 10.1161/CIRCRESAHA.110.218867. PubMed PMID: 20634488; PubMed Central PMCID: PMCPMC4254700.
  17. Liu J, Shen JX, Hu JL, Huang WH, Zhang GJ. Significance of interleukin-33 and its related cytokines in patients with breast cancers. Front Immunol. 2014;5:141. doi: 10.3389/fimmu.2014.00141. PubMed PMID: 24778632; PubMed Central PMCID: PMCPMC3985005.
  18. Schwartz C, O’Grady K, Lavelle EC, Fallon PG. Interleukin 33: an innate alarm for adaptive responses beyond Th2 immunity-emerging roles in obesity, intestinal inflammation, and cancer. Eur J Immunol. 2016;46:1091-100. doi: 10.1002/eji.201545780. PubMed PMID: 27000936.
  19. Chen XJ, Huang YD, Li N, Chen M, Liu F, Pu D, et al. Correlations between serum IL33 and tumor development: a meta-analysis. Asian Pac J Cancer Prev. 2014;15:3503-5. doi: 10.7314/apjcp.2014.15.8.3503. PubMed PMID: 24870747.
  20. Farjam M, Bahrami H, Bahramali E, Jamshidi J, Askari A, Zakeri H, et al. A cohort study protocol to analyze the predisposing factors to common chronic non-communicable diseases in rural areas: Fasa Cohort Study. BMC Public Health. 2016;16:1090. doi: 10.1186/s12889-016-3760-z. PubMed PMID: 27756262; PubMed Central PMCID: PMCPMC5069851.
  21. Kazemi M, Bazyar M, Naghizadeh MM, Dehghan A, Rahimabadi MS, Chijan MR, et al. Lipid profile dysregulation in opium users based on Fasa PERSIAN cohort study results. Sci Rep. 2021;11:12058. doi: 10.1038/s41598-021-91533-4. PubMed PMID: 34103610; PubMed Central PMCID: PMCPMC8187592.
  22. Poustchi H, Eghtesad S, Kamangar F, Etemadi A, Keshtkar AA, Hekmatdoost A, et al. Prospective Epidemiological Research Studies in Iran (the PERSIAN Cohort Study): Rationale, Objectives, and Design. Am J Epidemiol. 2018;187:647-55. doi: 10.1093/aje/kwx314. PubMed PMID: 29145581; PubMed Central PMCID: PMCPMC6279089.
  23. Eghtesad S, Mohammadi Z, Shayanrad A, Faramarzi E, Joukar F, Hamzeh B, et al. The PERSIAN Cohort: Providing the Evidence Needed for Healthcare Reform. Arch Iran Med. 2017;20:691-5. PubMed PMID: 29480734.
  24. Firouzabadi N, Dashti M, Dehshahri A, Bahramali E. Biomarkers of IL-33 and sST2 and Lack of Association with Carvedilol Therapy in Heart Failure. Clin Pharmacol. 2020;12:53-8. doi: 10.2147/CPAA.S256290. PubMed PMID: 32607003; PubMed Central PMCID: PMCPMC7305854.
  25. Firouzabadi N, Haghnegahdar M, Khalvati B, Dehshahri A, Bahramali E. Overexpression of Adiponectin Receptors in Opium Users with and without Cancer. Clin Pharmacol. 2020;12:59-65. doi: 10.2147/CPAA.S256289. PubMed PMID: 32607004; PubMed Central PMCID: PMCPMC7304683.
  26. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436-44. doi: 10.1038/nature07205. PubMed PMID: 18650914.
  27. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883-99. doi: 10.1016/j.cell.2010.01.025. PubMed PMID: 20303878; PubMed Central PMCID: PMCPMC2866629.
  28. Ecimovic P, Murray D, Doran P, McDonald J, Lambert DG, Buggy DJ. Direct effect of morphine on breast cancer cell function in vitro: role of the NET1 gene. Br J Anaesth. 2011;107:916-23. doi: 10.1093/bja/aer259. PubMed PMID: 21857017.
  29. Mathew B, Lennon FE, Siegler J, Mirzapoiazova T, Mambetsariev N, Sammani S, et al. The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg. 2011;112:558-67. doi: 10.1213/ANE.0b013e31820568af. PubMed PMID: 21156980; PubMed Central PMCID: PMCPMC4327979.
  30. Nylund G, Pettersson A, Bengtsson C, Khorram-Manesh A, Nordgren S, Delbro DS. Functional expression of mu-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon. Dig Dis Sci. 2008;53:461-6. doi: 10.1007/s10620-007-9897-y. PubMed PMID: 17680363.
  31. Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: a review. Am J Ther. 2004;11:354-65. doi: 10.1097/01.mjt.0000132250.95650.85. PubMed PMID: 15356431.
  32. Peterson PK, Molitor TW, Chao CC. The opioid-cytokine connection. J Neuroimmunol. 1998;83:63-9. doi: 10.1016/s0165-5728(97)00222-1. PubMed PMID: 9610674.
  33. Carr DJ, DeCosta BR, Kim CH, Jacobson AE, Guarcello V, Rice KC, et al. Opioid receptors on cells of the immune system: evidence for delta- and kappa-classes. J Endocrinol. 1989;122:161-8. doi: 10.1677/joe.0.1220161. PubMed PMID: 2549147.
  34. Miller AM. Role of IL-33 in inflammation and disease. J Inflamm (Lond). 2011;8:22. doi: 10.1186/1476-9255-8-22. PubMed PMID: 21871091; PubMed Central PMCID: PMCPMC3175149.
  35. Bergis D, Kassis V, Ranglack A, Koeberle V, Piiper A, Kronenberger B, et al. High Serum Levels of the Interleukin-33 Receptor Soluble ST2 as a Negative Prognostic Factor in Hepatocellular Carcinoma. Transl Oncol. 2013;6:311-8. doi: 10.1593/tlo.12418. PubMed PMID: 23730411; PubMed Central PMCID: PMCPMC3660800.
  36. Cui G, Ren J, Xu G, Li Z, Zheng W, Yuan A. Cellular and clinicopathological features of the IL-33/ST2 axis in human esophageal squamous cell carcinomas. Cancer Cell Int. 2018;18:203. doi: 10.1186/s12935-018-0700-2. PubMed PMID: 30559604; PubMed Central PMCID: PMCPMC6290492.
  37. Sun P, Ben Q, Tu S, Dong W, Qi X, Wu Y. Serum interleukin-33 levels in patients with gastric cancer. Dig Dis Sci. 2011;56:3596-601. doi: 10.1007/s10620-011-1760-5. PubMed PMID: 21643739.
  38. Jovanovic IP, Pejnovic NN, Radosavljevic GD, Arsenijevic NN, Lukic ML. IL-33/ST2 axis in innate and acquired immunity to tumors. Oncoimmunology. 2012;1:229-31. doi: 10.4161/onci.1.2.18131. PubMed PMID: 22720252; PubMed Central PMCID: PMCPMC3376988.
  39. Yu XX, Hu Z, Shen X, Dong LY, Zhou WZ, Hu WH. IL-33 Promotes Gastric Cancer Cell Invasion and Migration Via ST2-ERK1/2 Pathway. Dig Dis Sci. 2015;60:1265-72. doi: 10.1007/s10620-014-3463-1. PubMed PMID: 25655003.
  40. Yue Y, Lian J, Wang T, Luo C, Yuan Y, Qin G, et al. Interleukin-33-nuclear factor-kappaB-CCL2 signaling pathway promotes progression of esophageal squamous cell carcinoma by directing regulatory T cells. Cancer Sci. 2020;111:795-806. doi: 10.1111/cas.14293. PubMed PMID: 31883400; PubMed Central PMCID: PMCPMC7060484.
  41. Zhang JF, Wang P, Yan YJ, Li Y, Guan MW, Yu JJ, et al. IL33 enhances glioma cell migration and invasion by upregulation of MMP2 and MMP9 via the ST2-NF-kappaB pathway. Oncol Rep. 2017;38:2033-42. doi: 10.3892/or.2017.5926. PubMed PMID: 28849217; PubMed Central PMCID: PMCPMC5652951.
  42. Gao X, Wang X, Yang Q, Zhao X, Wen W, Li G, et al. Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells. J Immunol. 2015;194:438-45. doi: 10.4049/jimmunol.1401344. PubMed PMID: 25429071; PubMed Central PMCID: PMCPMC4272901.
  43. Balkwill F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev. 2006;25:409-16. doi: 10.1007/s10555-006-9005-3. PubMed PMID: 16951987.
  44. Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature. 2015;522:345-8. doi: 10.1038/nature14282. PubMed PMID: 25822788; PubMed Central PMCID: PMCPMC4475637.
  45. Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010;10:103-10. doi: 10.1038/nri2692. PubMed PMID: 20081870.
  46. Hu LA, Fu Y, Zhang DN, Zhang J. Serum IL-33 as a diagnostic and prognostic marker in non- small cell lung cancer. Asian Pac J Cancer Prev. 2013;14:2563-6. doi: 10.7314/apjcp.2013.14.4.2563. PubMed PMID: 23725175.
  47. Hayakawa H, Hayakawa M, Kume A, Tominaga S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem. 2007;282:26369-80. doi: 10.1074/jbc.M704916200. PubMed PMID: 17623648.
  48. Oshikawa K, Yanagisawa K, Tominaga S, Sugiyama Y. Expression and function of the ST2 gene in a murine model of allergic airway inflammation. Clin Exp Allergy. 2002;32:1520-6. doi: 10.1046/j.1365-2745.2002.01494.x. PubMed PMID: 12372135.