Role of Interleukin-18 in Thyroid tumorigenesis

Toral Kobawala, Trupti Trivedi, Kinjal Gajjar, Girish Patel, Nandita Ghosh

Abstract


Purpose: Although the significance of Interleukin-18 (IL-18) has been studied in pathogenesis of different cancers including, ovarian, gastric, breast, lung carcinoma and melanoma, its role in thyroid cancer- the most common endocrine malignancy has not yet been looked at extensively. Hence, this study intended to examine the role of IL-18 in thyroid tumorigenesis.

Methods: Sixty seven patients with benign thyroid diseases and 106 thyroid cancer patients (including 83 papillary, 6 follicular, 9 medullary and 8 anaplastic thyroid carcinoma patients) were enrolled in the study. To accomplish the aim, the circulating levels of IL-18 were estimated by enzyme linked immunosorbent assay (ELISA) from all patients and compared with controls. Further, protein expression of IL-18 was determined from the primary tumors of the patients using immunohistochemistry.

Results: It was observed that the circulating levels of IL-18 were significantly higher in all patients: benign thyroid diseases (p = 0.006), papillary (p < 0.001), follicular (p = 0.023), medullary (p = 0.002) and anaplastic thyroid cancer (p < 0.001) than the controls. In addition to this, IL-18 could well discriminate papillary (AUC = 0.627, p =0.008) and anaplastic thyroid carcinoma patients (AUC = 0.777, p = 0.011) from patients with benign thyroid diseases. However, the difference between tumoral protein expression of IL-18 in patients with benign thyroid diseases and thyroid carcinoma was not significant. The Kaplan - Meier survival analysis revealed that neither the circulating nor the tumoral protein expression of IL-18 was the significant predictor of disease free survival (DFS) or overall survival (OS) in papillary thyroid cancer patients.

Conclusion: Though not a significant prognosticator, circulating IL-18 may be useful as a differentiating factor in thyroid tumorigenesis and the increase in serum IL-18 levels may be provoked in response to the tumor. Thus, including IL-18 along with the current treatment practice may have a significant role in better management of the disease. However, further exploration of this interleukin is required in a larger series of patients with longer follow up period.


Keywords


IL-18, Thyroid tumorigenesis, Papillary thyroid cancer, Immuno- histochemistry, ELISA

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References


Park S, Cheon S, Cho D. The dual effects of interleukin-18 in tumor progression. Cell Mol Immunol. 2007;4(5):329-35.

Vidal-Vanaclocha F, Mendoza L, Telleria N, et al. Clinical and experimental approaches to the pathophysiology of interleukin-18 in cancer progression. Cancer Metastasis Rev. 2006;25(3):417-34.

Nakanishi K, Yoshimoto T, Tsutsui H, et al. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immuno. 2001;19:423-74.

Akahira JI, Konno R, Ito K, et al. Impact of serum interleukin-18 level as a prognostic indicator in patients with epithelial ovarian carcinoma. Int J Clin Oncol. 2004;9(1):42-6.

Azam T, Novick D, Bufler P, et al. Identification of a critical Ig-like domain in IL-18 receptor α and characterization of a functional IL-18 receptor complex. J Immunol. 2003;171(12):6574-80.

Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14(6):e218-28.

Merendino R, Gangemi S, Ruello A, et al. Serum levels of interleukin-18 and sICAM-1 in patients affected by breast cancer: preliminary considerations. Int J Biol Markers. 2001;16(2):126-9.

Jiang D, Liu W, Lu Y, et al. Function of IL-18 in promoting metastasis of lung cancer. Chinese Journal of Oncology. 2003;25(4):348-52.

Eissa S, Zaki SA, El-Maghraby SM, et al. Importance of serum IL-18 and RANTES as markers for breast carcinoma progression. J Egypt Natl Canc Inst. 2005;17(1):51-5.

Jung MK, Song HK, Kim K-E, et al. IL-18 enhances the migration ability of murine melanoma cells through the generation of ROI and the MAPK pathway. Immunol Lett. 2006;15;107(2):125-30.

Ye ZB, Ma T, Li H, et al. Expression and significance of intratumoral interleukin-12 and interleukin-18 in human gastric carcinoma. World J Gastroenterol. 2007;13(11):1747-51.

Medina L, Rabinovich A, Piura B, et al. Expression of IL-18, IL-18 Binding Protein, and IL-18 Receptor by Normal and Cancerous Human Ovarian Tissues: Possible Implication of IL-18 in the Pathogenesis of Ovarian Carcinoma. Mediators Inflamm. 2014;2014:914954.

Kobawala TP, Trivedi TI, Gajjar KK, et al. 2016. Significance of TNF-α and the adhesion molecules: L-Selectin and VCAM-1 in papillary thyroid carcinoma. J Thyroid Res. 2016;2016: 8143695.

Kobawala TP, Trivedi TI, Gajjar KK, et al. Significance of Interleukin-6 in Papillary Thyroid Carcinoma. J Thyroid Res. 2016;2016:6178921.

Remmele W, Stegner H. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Der Pathologe. 1987;8(3):138-40.

Lissoni P, Brivio F, Rovelli F, et al. Serum concentrations of interleukin-18 in early and advanced cancer patients: enhanced secretion in metastatic disease. J Biol Regul Homeost Agents. 2000;14(4):275-7.

Kawabata T, Ichikura T, Majima T, et al. Preoperative serum interleukin‐18 level as a postoperative prognostic marker in patients with gastric carcinoma. Cancer. 2001;92(8):2050-5.

Bukan N, Sozen S, Coskun U, et al. Serum interleukin‐18 and nitric oxide activity in bladder carcinoma. Eur Cytokine Netw. 2003;14(3):163-7.

Gunel N, Coskun U, Sancak B, et al. Prognostic value of serum IL-18 and nitric oxide activity in breast cancer patients at operable stage. Am J Clin Oncol. 2003;26(4):416-21.

Alexandrakis M, Passam F, Sfiridaki K, et al. Interleukin-18 in multiple myeloma patients: serum levels in relation to response to treatment and survival. Leuk Res. 2004;28(3):259-66.

Martone T, Bellone G, Pagano M, et al. Constitutive expression of interleukin‐18 in head and neck squamous carcinoma cells. Head Neck. 2004;26(6):494-503.

Naumnik W, Chyczewska E, Kovalchuk O, et al. Serum levels of interleukin-18 (IL-18) and soluble interleukin-2 receptor (sIL-2R) in lung cancer. Rocz Akad Med Bialymst. 2004;49:246-51.

Riedel F, Adam S, Feick P, et al. Expression of IL-18 in patients with head and neck squamous cell carcinoma. Int J Mol Med. 2004;13(2):267-72.

Sozen S, Coskun U, Sancak B, et al. Serum levels of interleukin-18 and nitrite+ nitrate in renal cell carcinoma patients with different tumor stage and grade. Neoplasma. 2004;51(1):25-9.

Tsuboi K, Miyazaki T, Nakajima M, et al. Serum interleukin-12 and interleukin-18 levels as a tumor marker in patients with esophageal carcinoma. Cancer Lett. 2004;205(2):207-14.

Kiersnowska-Rogowska B, Izycka A, Jablonska E, et al. Estimation of level of soluble form PECAM-1, ICAM-2 and TNF-alpha, IL-18 in serum patients with chronic myelogenic leukemia. Przeglad Lekarski. 2005;62(8):772-4.

Asakawa M, Kono H, Amemiya H, et al. Role of interleukin‐18 and its receptor in hepatocellular carcinoma associated with hepatitis C virus infection. Int J Cancer. 2006;118(3):564-70.

Bellone G, Smirne C, Mauri FA, et al. Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: implications for survival. Cancer Immunol Immunother. 2006;55(6):684-698.

Diakowska D, Markocka-Maczka K, Grabowski K, et al. Serum interleukin-12 and interleukin-18 levels in patients with oesophageal squamous cell carcinoma. Exp Oncol. 2006;28(4):319-22.

Tangkijvanich P, Thong-Ngam D, Mahachai V, et al. Role of serum interleukin-18 as a prognostic factor in patients with hepatocellular carcinoma. World J Gastroenterol. 2007;13(32):4345-9.

Cheng KS, Tang HL, Chou FT, et al. Cytokine evaluation in liver cirrhosis and hepatocellular carcinoma. Hepatogastroenterology. 2009;56(93):1105-10.

Haghshenas MR, Hosseini SV, Mahmoudi M, et al. IL‐18 serum level and IL‐18 promoter gene polymorphism in Iranian patients with gastrointestinal cancers. J Gastroenterol Hepatol. 2009;24(6):1119-22.

Okamoto M, Azuma K, Hoshino T, et al. Correlation of decreased survival and IL-18 in bone metastasis. Intern Med. 2009;48(10):763-73.

Perrella O, Cuomo O, Sbreglia C, et al. IL-18 and interferon-gamma in HCV-related hepatocellular carcinoma: a model of interplay between immune status and cancer. J Biol Regul Homeost Agents. 2009;23(4):251-8.

Dehaghani AS, Shahriary K, Kashef MA, et al. Interleukin-18 gene promoter and serum level in women with ovarian cancer. Mol Biol Rep. 2009;36(8):2393-7.

Metwally FM, EL-mezayen HA, Ahmed HH. Significance of vascular endothelial growth factor, interleukin-18 and nitric oxide in patients with breast cancer: correlation with carbohydrate antigen 15.3. Med Oncol. 2011;28 Suppl 1:S15-21.

Orengo AM, Fabbi M, Miglietta L, et al. Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor. Int J Cancer. 2011;129(5):1116-25.

Jaiswal PK, Singh V, Srivastava P, et al. Association of IL-12, IL-18 variants and serum IL-18 with bladder cancer susceptibility in North Indian population. Gene. 2013;519(1):128-34.

Pappa C, Alexandrakis M, Boula A, et al. Emerging roles of endoglin/CD105 and angiogenic cytokines for disease development and progression in multiple myeloma patients. Hematol Oncol. 2013;31(4):201-5.

Tsirakis G, Pappa CA, Kaparou M, et al. The relationship between soluble receptor of interleukin-6 with angiogenic cytokines and proliferation markers in multiple myeloma. Tumor Biol. 2013;34(2):859-64.

Bayhan Z, Simşek T, Ergul E, et al. Serum cytokine levels in patients with colorectal cancers according to tumor stages and VEGF gene polymorphism. Hepatogastroenterol. 2014;61(135):1889-94.

Tas F, Yasasever CT, Karabulut S, et al. Clinical significance of serum interleukin-18 (IL-18) levels in patients with gastric cancer. Biomed Pharmacother. 2015;70:19-23.

Matveeva L, Mosina L. Serum interleukin-18 level in precancerous conditions and gastric cancer. Experimental & Clinical Gastroenterology. 2013;6:21-4.

Dwivedi S, Goel A, Natu SM, et al. Diagnostic and prognostic significance of prostate specific antigen and serum interleukin 18 and 10 in patients with locally advanced prostate cancer: a prospective study. Asian Pac J Cancer Prev. 2011;12(7):1843-8.

Thong-Ngam D, Tangkijvanich P, Lerknimitr R, et al. Diagnostic role of serum interleukin-18 in gastric cancer patients. World J Gastroenterol. 2006;12(28):4473-7.

Bao J, Lu Y, Deng Y, et al. Association between IL-18 polymorphisms, serum levels, and HBV-related hepatocellular carcinoma in a Chinese population: a retrospective case–control study. Cancer Cell Int. 2015;15(1):1.

Kaya C, Pabuccu R, Berker B, et al. Plasma interleukin-18 levels are increased in the polycystic ovary syndrome: relationship of carotid intima-media wall thickness and cardiovascular risk factors. Fertil Steril. 2010;93(4):1200-7.

Yang Y, Qiao J, Li R, et al. Is interleukin-18 associated with polycystic ovary syndrome. Reprod Biol Endocrinol. 2011;9(1):7.

Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation. 2001;104(14):1598-603.

Esposito K, Pontillo A, Ciotola M, et al. Weight loss reduces interleukin-18 levels in obese women. J of Clin Endocrinol Metab. 2002;87(8):3864-6.

Kawasaki D, Tsujino T, Morimoto S, et al. Usefulness of circulating interleukin-18 concentration in acute myocardial infarction as a risk factor for late restenosis after emergency coronary angioplasty. Am J Cardiol. 2003;91(10):1258-61.

Srabovic N, Mujagic Z, Mujanovic-Mustedanagic J, et al. Interleukin 18 expression in the primary breast cancer tumour tissue. Med Glas (Zenica). 2011;8(1):109-15.

Chia CS, Ban K, Ithnin H, et al. Expression of interleukin-18, interferon-γ and interleukin-10 in hepatocellular carcinoma. Immunol Lett. 2002;84(3):163-72.

Cui G, Goll R, Olsen T, et al. Reduced expression of microenvironmental Th1 cytokines accompanies adenomas–carcinomas sequence of colorectum. Cancer Immunol Immunother. 2007;56(7):985-95.

Szaflarska A, Szczepanik A, Siedlar M, et al. Preoperative plasma level of IL-10 but not of proinflammatory cytokines is an independent prognostic factor in patients with gastric cancer. Anticancer Res. 2009;29(12):5005-12.

Liu W, Hu M, Wang Y, et al. Overexpression of interleukin-18 protein reduces viability and induces apoptosis of tongue squamous cell carcinoma cells by activation of glycogen synthase kinase-3β signaling. Oncol Rep. 2015;33(3):1049-56.

Fabbi M, Carbotti G, Ferrini S. Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP. J Leukoc Biol. 2015;97(4):665-75.

Ma Z, Li W, Yoshiya S, et al. Augmentation of Immune Checkpoint Cancer Immunotherapy with IL-18. Clinical Cancer Res. 2016;22(12):2969-80.




DOI: http://dx.doi.org/10.14319/ijcto.44.1

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