Hakan SOYLU, Betül ÜNAL, Kubra AKSU ISTIL, Kayihan KARACOR, Özge BEYAZÇİÇEK, İsmail ÜSTÜNEL

Characterization of Apelin/APJ Axis Expression in Normal Testicular Tissue, Germ Cell Neoplasia in Situ, and Testicular Seminoma

Anahtar Kelimeler:

Apelin, APJ, GCNIS, Seminoma, Testis

Characterization of Apelin/APJ Axis Expression in Normal Testicular Tissue, Germ Cell Neoplasia in Situ, and Testicular Seminoma

Aim: A testicular germ cell tumour is not observed widely, but its incidence and mortality rates have increased in recent years. One of the most common forms of this tumour is seminoma. Germ cell neoplasia in situ (GCNIS) is the precursor of seminoma. The apelin/APJ axis is increased in many cancers and is a pathway that plays an active role in angiogenesis, lymphangiogenesis, tumour growth, and migration. This study investigated the cellular distributions of apelin and APJ protein expressions in normal testicular tissue (TT), GCNIS, and seminoma.Material and Methods: Tissues from 18 patients who had undergone orchiectomy were used in this study. These tissues include areas of normal TT, GCNIS, and seminoma. Immunolocalisation of apelin and APJ were identified through the immunohistochemical method.Results: Apelin expression was significantly increased in seminoma and GCNIS compared to normal. Apelin expression were the same in GCNIS and seminoma. APJ expression was significantly increased in seminoma compared to normal and GCNIS. Normal and GCNIS APJ expressions were similar.Conclusion: Expressions of apelin and APJ proteins were significantly increased in seminoma in our study. Our findings were consistent with the results of relevant studies as increased expression of apelin/APJ has been observed in many different cancers. It can be predicted that the increase of this pathway in seminoma may support angiogenesis, lymphangiogenesis, migration, and metastasis. Therefore, the increase in mortality rates in seminoma patients may be related to apelin/APJ axis. Ultimately, the use of inhibitors of this pathway in these patients may reduce their mortality rate. New studies are needed before these inhibitors can be used clinically.

Keywords:

Apelin, APJ, GCNIS, Seminoma, Testis,

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1. Cedeno JD, Light DE, Leslie SW. Testicular Seminoma. StatPearls. Treasure Island (FL) 2022
2. Almstrup K, Hoei-Hansen CE, Nielsen JE, et al. Genome-wide gene expression profiling of testicular carcinoma in situ progression into overt tumours. Br J Cancer. 2005;92:1934-41.
3. Looijenga LHJ, Kao CS, Idrees MT. Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology. Int J Mol Sci. 2019;20.
4. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7-33.
5. Woldu SL, Bagrodia A. Update on epidemiologic considerations and treatment trends in testicular cancer. Curr Opin Urol. 2018;28:440-7.
6. Znaor A, Lortet-Tieulent J, Jemal A, Bray F. International variations and trends in testicular cancer incidence and mortality. Eur Urol. 2014;65:1095-106.
7. Cheng L, Albers P, Berney DM, et al. Testicular cancer. Nat Rev Dis Primers. 2018;4:29.
8. Cui Y, Miao C, Liu S, et al. Clusterin suppresses invasion and metastasis of testicular seminoma by upregulating COL15a1. Mol Ther Nucleic Acids. 2021;26:1336-50.
9. Albers P, Albrecht W, Algaba F, et al. Guidelines on Testicular Cancer: 2015 Update. Eur Urol. 2015;68:1054-68.
10. Berta J, Hoda MA, Laszlo V, et al. Apelin promotes lymphangiogenesis and lymph node metastasis. Oncotarget. 2014;5:4426-37.
11. Antushevich H, Wojcik M. Review: Apelin in disease. Clin Chim Acta. 2018;483:241-8.
12. Hu D, Cui Z, Peng W, et al. Apelin is associated with clinicopathological parameters and prognosis in breast cancer patients. Arch Gynecol Obstet. 2022;306:1185-95.
13. Akinci B, Celtik A, Tunali S, et al. Circulating apelin levels are associated with cardiometabolic risk factors in women with previous gestational diabetes. Arch Gynecol Obstet. 2014;289:787-93.
14. Rayalam S, Della-Fera MA, Kasser T, et al. Emerging role of apelin as a therapeutic target in cancer: a patent review. Recent Pat Anticancer Drug Discov. 2011;6:367-72.
15. Kleinz MJ, Davenport AP. Emerging roles of apelin in biology and medicine. Pharmacol Ther. 2005;107:198-211.
16. Berta J, Kenessey I, Dobos J, et al. Apelin expression in human non-small cell lung cancer: role in angiogenesis and prognosis. J Thorac Oncol. 2010;5:1120-9.
17. Yang L, Li YL, Li XQ, Zhang Z. High apelin level indicates a poor prognostic factor in muscle-invasive bladder cancer. Dis Markers. 2019;2019:4586405.
18. Kalin RE, Kretz MP, Meyer AM, et al. Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis. Dev Biol. 2007;305:599-614.
19. Eyries M, Siegfried G, Ciumas M, et al. Hypoxia-induced apelin expression regulates endothelial cell proliferation and regenerative angiogenesis. Circ Res. 2008;103:432-40.
20. Facciabene A, Peng X, Hagemann IS, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 2011;475:226-30.
21. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nature Reviews Cancer. 2011;11:393-410.
22. Hall C, Ehrlich L, Venter J, et al. Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth. Cancer Lett. 2017;386:179-88.
23. Aktan M, Ozmen HK. A preliminary study of serum apelin levels in patients with head and neck cancer. Eurasian J Med. 2019;51:57-9.
24. Wan Y, Zeng ZC, Xi M, et al. Dysregulated microRNA-224/apelin axis associated with aggressive progression and poor prognosis in patients with prostate cancer. Hum Pathol. 2015;46:295-303.
25. Hoffmann M, Fiedor E, Ptak A. Bisphenol A and its derivatives tetrabromobisphenol A and tetrachlorobisphenol A induce apelin expression and secretion in ovarian cancer cells through a peroxisome proliferator-activated receptor gamma-dependent mechanism. Toxicol Lett. 2017;269:15-22.
26. Salman T, Demir L, Varol U, et al. Serum apelin levels and body composition changes in breast cancer patients treated with an aromatase inhibitor. J BUON. 2016;21:1419-24.
27. Diakowska D, Markocka-Maczka K, Nienartowicz M, et al. Assessment of apelin, apelin receptor, resistin, and adiponectin levels in the primary tumor and serum of patients with esophageal squamous cell carcinoma. Adv Clin Exp Med. 2019;28:671-8.
28. Maden M, Pamuk ON, Pamuk GE. High apelin levels could be used as a diagnostic marker in multiple myeloma: A comparative study. Cancer Biomark. 2016;17:391-6.
29. Harford-Wright E, Andre-Gregoire G, Jacobs KA, et al. Pharmacological targeting of apelin impairs glioblastoma growth. Brain. 2017;140:2939-54.
30. Podgorska M, Diakowska D, Pietraszek-Gremplewicz K, et al. Evaluation of apelin and apelin receptor level in the primary tumor and serum of colorectal cancer patients. J Clin Med. 2019;8:1513.
31. Feng M, Yao G, Yu H, et al. Tumor apelin, not serum apelin, is associated with the clinical features and prognosis of gastric cancer. BMC Cancer. 2016;16:794.
32. Diakowska D, Markocka-Maczka K, Szelachowski P, Grabowski K. Serum levels of resistin, adiponectin, and apelin in gastroesophageal cancer patients. Dis Markers. 2014;2014:619649.
33. Tolkach Y, Ellinger J, Kremer A, et al. Apelin and apelin receptor expression in renal cell carcinoma. Br J Cancer. 2019;120:633-9.
34. Soylu H, Acar N, Ozbey O, et al. Characterization of notch signalling pathway members in normal prostate, prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma. Pathol Oncol Res. 2016;22:87-94.
35. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29.
36. Masoumi J, Jafarzadeh A, Khorramdelazad H, et al. Role of Apelin/APJ axis in cancer development and progression. Adv Med Sci. 2020;65:202-13.
37. Muto J, Shirabe K, Yoshizumi T, et al. The apelin-APJ system induces tumor arteriogenesis in hepatocellular carcinoma. Anticancer Res. 2014;34:5313-20.
38. Mastrella G, Hou M, Li M, et al. Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma. Cancer Res. 2019;79:2298-313.
39. Le Gonidec S, Chaves-Almagro C, Bai Y, et al. Protamine is an antagonist of apelin receptor, and its activity is reversed by heparin. FASEB J. 2017;31:2507-19.