Bekir Ucan, Muhammed Kizilgul, Mustafa Sahin, Mustafa Ozbek, Seyda Ozdemir, Erman Cakal

Tiroid kanserinde düşük plazminojen aktivatör inhibitör-1 düzeyleri: Kanser gelişiminde uPA/PAI-1 paradoksu

Amaç: Plazminojen aktivatör inhibitor-1 (PAI-1) hücre migrasyon ve apoptozisinin güçlü inhibitörüdür. Çoğu kanser türünde yüksek PAI-1 düzeyleri tespit edilmiştir. Bir çok çalışmada tiroid kanserlerinde artmış PAI-1 ekspresyonu ve bunun kötü klinik sonuçlarla ilişkili olduğu gösterilmiştir. Bu çalışmada papiller tiroid kanserlerinde(PTK) serum PAI-1 düzeylerini ve bunun PTK gelişimi ve boyutu üzerine etkisini araştırmak amaçlanmıştır.

Anahtar Kelimeler:

papiller tiroid kanseri, ürokinaz plazminojen aktivatörü, Plazminojen aktivatör inhibitor-1

Low plasminogen activator inhibitor-1 levels in thyroid carcinoma: uPA/PAI-1 paradox in cancer proggression

Aim: Plasminogen activator inhibitor-1 (PAI-1) potently inhibits cell migration and apoptosis. Increased levels of PAI-1 were demonstrated in a great variety of cancers. Many studies demonstrated increased expression of PAI-1 in thyroid cancer and its relation to unfavorable clinical outcome. In this study, we aimed to investigate serum PAI-1 levels in patients with papillary thyroid carcinoma (PTC) as well as its effect in development and size of PTC.Material and methods: Fifty-four papillary thyroid cancer patients (7 male, 47 female) and 24 healthy controls (6 male, 18 female) were enrolled in the study. Groups were compared by demographic, anthropometric, biochemical data, and by serum ghrelin levels. Serum PAI-1 levels were measured by enzyme-linked immunosorbent assay (ELISA).Results: Mean age were similar between PTC and control group (42.4 ± 10.1 to 42.5 ± 8.9, p:0.794). Serum PAI-1 levels were lower in patients with PTC when compared to healthy controls (241.34 ± 107.82 to 327.24 ± 138.51, p:0.011). BMI, Homa-IR and TSH, FT4, anti-TPO, anti-Tg, total cholesterol, triglyceride, HDL-Cholesterol, LDL-Cholesterol, calcium, phosphorus, 25-OH-VitD, parathormone, glucose, insülin concentrations were similar between groups (p>0.05). PAI-1 concentrations were not correlated with clinical, biochemical and hormonal parameters except parathormone (PTH) concentrations in PTC group (r:-0.446, p:0.0027).Conclusions: Serum PAI-1 levels were lower in patients with papillary thyroid carcinoma. Our results might support the thesis of PAI-1 is expected to suppress cancer progression due to its ability to inhibit urokinase plasminogen activator activity.

Keywords:

Plasminogen activator inhibitor-1, papillary thyroid carcinoma, urokinase plasminogen activator,

PDF

___

1. Ulisse S, Baldini E, Sorrenti S, D’Armiento M. The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr Cancer Drug Targets. 2009;9(1):32–71. 2. Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature. 1996;383(6599):441–3. 3. Kjøller L, Kanse SM, Kirkegaard T, Rodenburg KW, Rønne E, Goodman SL, et al. Plasminogen activator inhibitor-1 represses integrin- and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp Cell Res. 1997;232(2):420–9. 4. Kwaan HC, Wang J, Svoboda K, Declerck PJ. Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br J Cancer. 2000;82(10):1702–8. 5. Gutierrez LS, Schulman A, Brito-Robinson T, Noria F, Ploplis VA, Castellino FJ. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Cancer Res. 2000;60(20):5839–47. 6. Allgayer H, Heiss MM, Schildberg FW. Prognostic factors in gastric cancer. Br J Surg. 1997;84(12):1651–64. 7. Berger DH. Plasmin/plasminogen system in colorectal cancer. In: World Journal of Surgery. 2002. p. 767–71. 8. Look MP, van Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, et al. Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst. 2002;94(2):116–28. 9. Kuhn W, Schmalfeldt B, Reuning U, Pache L, Berger U, Ulm K, et al. Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIc. Br J Cancer. 1999;79(11–12):1746–51. 10. Pavey SJ, Hawson G a, Marsh N a. Impact of the fibrinolytic enzyme system on prognosis and survival associated with non-small cell lung carcinoma. Blood Coagul Fibrinolysis. 2001;12(1):51–8. 11. Chen S-C, Henry DO, Reczek PR, Wong MKK. Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis. Mol Cancer Ther. 2008;7(5):1227–36. 12. Eitzman DT, Krauss JC, Shen T, Cui J, Ginsburg. Lack of plasminogen activator inhibitor-1 effect in a transgenic mouse model of metastatic melanoma. Blood. 1996;87(11):4718–22. 13. Almholt K, Nielsen BS, Frandsen TL, Brunner N, Dano K, Johnsen M. Metastasis of transgenic breast cancer in plasminogen activator inhibitor-1 gene-deficient mice. Oncogene. 2003;22(28):4389–97. 14. Ma D, Gerard RD, Li XY, Alizadeh H, Niederkorn JY. Inhibition of metastasis of intraocular melanomas by adenovirus-mediated gene transfer of plasminogen activator inhibitor type 1 (PAI-1) in an athymic mouse model. Blood. 1997;90(7):2738–46. 15. Hjortland GO, Bjørnland K, Pettersen S, Garman-Vik SS, Emilsen E, Nesland JM, et al. Modulation of glioma cell invasion and motility by adenoviral gene transfer of PAI-1. Clin Exp Metastasis. 2003;20(4):301–9. 16. Praus M, Wauterickx K, Collen D, Gerard RD. Reduction of tumor cell migration and metastasis by adenoviral gene transfer of plasminogen activator inhibitors. Gene Ther. 1999;6(2):227–36. 17. Ulisse S, Baldini E, Toller M, Marchioni E, Giacomelli L, De Antoni E, et al. Differential expression of the components of the plasminogen activating system in human thyroid tumour derived cell lines and papillary carcinomas. Eur J Cancer. 2006;42(15):2631–8. 18. Ito Y, Takeda T, Kobayashi T, Wakasugi E, Tamaki Y, Umeshita K, et al. Plasminogen activation system in active even in thyroid tumors; an immunohistochemical study. Anticancer Res. 1996;16(1):81–9. 19. Kushlinskii NE, Gershtein ES, Kazantseva IA, Kharitidi Ti, Liakina LT, Kazakov SP, et al. [Plasminogen activators of urokinase and tissue types and their inhibitor (PAI-1) in cytosol fraction in thyroid diseases]. Vestn Ross Akad Med Nauk. 2001;(5):32–4. 20. Herceg GH, Herceg D, Kralik M, Bence-Žigman Z, Tomić-Brzac H, Kulić A. Urokinase-type plasminogen activator and its inhibitor in thyroid neoplasms: A cytosol study. Wien Klin Wochenschr. 2006;118(19–20):601–9. 21. Johnsen M, Lund LR, Rømer J, Almholt K, Danø K. Cancer invasion and tissue remodeling: Common themes in proteolytic matrix degradation. Vol. 10, Current Opinion in Cell Biology. 1998. p. 667–71. 22. Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des. 2004;10(1):39–49. 23. Andreasen PA, Kjoller L, Christensen L, Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer. 1997;72(1):1–22. 24. Schmitt M, Harbeck N, Thomssen C, Wilhelm O, Magdolen V, Reuning U, et al. Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. ThrombHaemost. 1997;78(0340–6245 (Print)):285–96. 25. Bajou K, Masson V, Gerard RD, Schmitt PM, Albert V, Praus M, et al. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin: Implications for antiangiogenic strategies. J Cell Biol. 2001;152(4):777–84. 26. Devy L, Blacher S, Grignet-Debrus C, Bajou K, Masson V, Gerard RD, et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J. 2002;16(2):147–54. 27. Czekay RP, Aertgeerts K, Curriden SA, Loskutoff DJ. Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol. 2003;160(5):781–91. 28. Jankun J, Keck RW, Skrzypczak-Jankun E, Swiercz R. Inhibitors of urokinase reduce size of prostate cancer xenografts in severe combined immunodeficient mice. Cancer Res. 1997;57(4):559–63. 29. McMahon GA, Petitclerc E, Stefansson S, Smith E, Wong MK, Westrick RJ, et al. Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis. J Biol Chem. 2001;276(36):33964–8. 30. Stefansson S, Petitclerc E, Wong MK, McMahon G a, Brooks PC, Lawrence D a. Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1. J Biol Chem. 2001;276(11):8135–41. 31. Horvatic Herceg G, Herceg D, Kralik M, Kulic A, Bence-Zigman Z, Tomic-Brzac H, et al. Urokinase plasminogen activator and its inhibitor type-1 as prognostic factors in differentiated thyroid carcinoma patients. Otolaryngol Head Neck Surg. 2013;149(4):533–40. 32. Ulisse S, Baldini E, Sorrenti S, Barollo S, Gnessi L, Catania A, et al. High expression of the urokinase plasminogen activator and its cognate receptor associates with advanced stages and reduced disease-free interval in papillary thyroid carcinoma. J Clin Endocrinol Metab. 2011;96(2):504–8. 33. Nowicki TS, Kummer NT, Iacob C, Suslina N, Schaefer S, Schantz S, et al. Inhibition of uPAR and uPA reduces invasion in papillary thyroid carcinoma cells. Laryngoscope. 2010;120(7):1383–90. 34. Kwaan HC, Mazar AP, McMahon BJ. The apparent uPA/PAI-1 paradox in cancer: More than meets the eye. Semin Thromb Hemost. 2013;39(4):382–91. 35. Binder BR, Mihaly J. The plasminogen activator inhibitor “paradox” in cancer. Vol. 118, Immunology Letters. 2008. p. 116–24. 36. McMahon BJ, Kwaan HC. Components of the plasminogen-plasmin system as biologic markers for cancer. In: Advances in Experimental Medicine and Biology. 2015. p. 145–56.