A Look To The Relationship Between Autophagy And Embryonal Carcinoma From A Different Perspective

Yıl 2025, Cilt: 6 Sayı: 1, 61 - 66, 15.03.2025

Şeyma Kipel , Hilal Nakkaş

Öz

Introduction: Testicular embryonal carcinoma is a type of testicular cancer that affects the germ cells which are the precursors of sperm cells that will eventually develop into sperm. These carcinoma cells are often aggressive. In such cells, autophagy may promote the survival and proliferation of cancer cells, as autophagy can help cells survive under stress. Autophagy may also allow cancer cells to develop resistance to their environment and to metastasize. ATG4 (Autophagy related 4) is a protein that plays a role in the initiation of autophagy. JAB1 (Jun activation domain binding protein 1) is a protein involved in cellular signaling and regulates many biological processes such as cell cycle, apoptosis, and gene expression. JAB1 is also involved in the regulation of the p27 protein, and its high expression can be observed in cancer cells. NEDL2 (Neuroepithelial differentiation marker like 2) is involved in cellular growth and developmental processes. It is also a protein that is thought to play a role in cancer progression. The aim of the study was to demonstrate expression and localization of ATG4, JAB1 and NEDL2 in testicular embryonal carcinoma cells.

Methods: The morphological examination of testis embryonal carcinoma cells were performed by using hematoxylin eosin (H-E) staining. Then, using the immunohistochemical technique, cellular expression and location of ATG4, JAB1 and NEDL2 in testis embryonal carcinoma cells were examined.

Results: According to immunohistochemistry results, ATG4, JAB1 and NEDL2 expression was detected in human testicular embryonal carcinoma cells.

Conclusions: By determining the expression levels of these three proteins, more information can be obtained about how important processes such as autophagy, cell cycle regulation and cellular development are affected in testicular embryonal carcinoma. This information could be an important step in understanding the biology of cancer and developing treatment strategies.

Anahtar Kelimeler

Testis embryonal carcinoma, autophagy, ATG4, JAB1, NEDL2

Otofaji Ve Embriyonel Karsinom Arasındaki İlişkiye Farklı Bir Perspektiften Bakış

Öz

Giriş: Testis embriyonal karsinom, sperme dönüşecek olan sperm hücrelerinin öncüleri olan germ hücrelerini etkileyen bir testis kanseri türüdür. Bu karsinom hücreleri genellikle agresiftir. Bu hücrelerde otofaji, hücrelerin stres altında hayatta kalmasına yardımcı olabileceğinden, kanser hücrelerinin hayatta kalmasını ve çoğalmasını destekleyebilir. Otofaji ayrıca kanser hücrelerinin çevrelerine karşı direnç geliştirmesine ve metastaz yapmasına izin verebilir. ATG4 (Autophagy related 4), otofajinin başlatılmasında rol oynayan bir proteindir. JAB1 (Jun activation domain binding protein 1), hücresel sinyalizasyon yer alan ve hücre döngüsü, apoptoz ve gen ifadesi gibi birçok biyolojik süreci düzenleyen bir proteindir. JAB1 ayrıca p27 proteininin düzenlenmesinde de yer alır ve yüksek ifadesi kanser hücrelerinde görülebilir. NEDL2 (Neuroepithelial differentiation marker like 2), hücresel büyüme ve gelişim süreçlerinde yer alır. Ayrıca kanser ilerlemesinde rol oynadığı düşünülen bir proteindir. Çalışmanın amacı, testis embriyonal karsinom hücrelerinde ATG4, JAB1 ve NEDL2'nin ekspresyonunu ve lokalizasyonunu göstermektir.

Yöntemler: Testis embriyonal karsinom hücrelerinin morfolojik incelemesi hematoksilen eozin (H-E) boyama kullanılarak yapıldı. Daha sonra, immünohistokimyasal teknik kullanılarak, testis embriyonal karsinom hücrelerinde ATG4, JAB1 ve NEDL2'nin hücresel ekspresyonu ve lokalizasyonu incelendi.

Bulgular: İmmünohistokimya sonuçlarına göre, insan testis embriyonal karsinom hücrelerinde ATG4, JAB1 ve NEDL2 ekspresyonu tespit edildi.

Sonuç: Bu üç proteinin ekspresyon seviyelerinin belirlenmesiyle, otofaji, hücre döngüsü regülasyonu ve hücresel gelişim gibi önemli süreçlerin testis embriyonal karsinomunda nasıl etkilendiği hakkında daha fazla bilgi elde edilebilir. Bu bilgi, kanser biyolojisinin anlaşılması ve tedavi stratejilerinin geliştirilmesinde önemli bir adım olabilir.

Anahtar Kelimeler

Testis embriyonal karsinom, otofaji, ATG4, JAB1, NEDL2

Kaynakça

• Baird D, Meyers G, Hu J. Testicular cancer: Diagnosis and treatment. American Family Physician 2018; 97(4), 261-8.
• Reuter V. Origins and molecular biology of testicular germ cell tumors. Modern Pathology 2005; 18(S2), S51–S60.
• Yorimitsu T, Klionsky D. Autophagy: molecular machinery for self-eating. Cell Death and Differentiation 2005;12(2), 154–60.
• Klionsky D.The moleculae of autophagy:unanswered questions. J Cell Sci 2005; 118(PT1):7-18.
• Maruyama T Noda N. Autophagy-regulating protease Atg4: structure, function, regulation and inhibition. The Journal of Antibiotics 2017; 71(1): 72–8.
• Chamovitz D, Segal D. JAB1/CSN5 and the COP9 signalosome. A complex situation. EMBO Rep 2001; 2(2):96–101.
• Shackleford T, Claret F. JAB1/CSN5: a new player in cell cycle control and cancer. Cell Division 2010; 5:26.
• Shen Q, Shang B, Jiang B, Wang Y, Wang Z, Chen G. Overexpression of JAB1 promotes malignant behavior and predicts poor prognosis in esophageal squamous cell carcinoma. Thorac Cancer 2020; 11(4):973–82.
• Rassidakis G, Claret F, Lai R, et al. Expression of p27(Kip1) and c-Jun activation binding protein 1 are inversely correlated in systemic anaplastic large cell lymphoma. Clinic Cancer Res 2003; 9(3), 1121–8.
• Tsuchida R, Miyauchi J, Shen L, et al. Expression of Cyclin‐dependent Kinase Inhibitor p27/Kipl and AP‐1 Coactivator p38/Jabl Correlates with Differentiation of Embryonal Rhabdomyosarcoma. Japanese Journal of Cancer Research 2005;93(9), 1000–6.
• Wang L, Zheng J, Pei D. The emerging roles of Jab1/CSN5 in cancer. Med Oncol 2016; 33(8):90.
• Wei R, Qiu X, Wang S, et al. NEDL2 is an essential regulator of enteric neural development and GDNF/Ret signaling. Cellular Signaling 2015;Volume 27, Issue 3, March 2015, Pages 578-86. Shen H, Kou Q, Shao L, Zhang J, Li F. E3 ubiquitin ligase HECW2: a promising target for tumour therapy. Cancer Cell 2024; Nov 11;24(1):374-84.
• Mao J, Zigo M, Zuidema D, Sutovsky M, Sutovsky P. NEDD4-like ubiquitin ligase 2 protein (NEDL2) in porcine spermatozoa, oocytes, and preimplantation embryos and its role in oocyte fertilization. Biology of Reproduction 2021; 104(1), 117–29.
• Wei R, Qiu X, Wang S, et al. NEDL2 is an essential regulator of enteric neural development and GDNF/Ret signaling. Cellular Signalling 2014; 27(3), 578–86.
• Tahri Y, Moueqqit O, Mokhtari M, Ramdani M, Nadir M, Bennani A, Barki A. Unusual presentation of embryonal carcinoma of the testis: a case report.Cureus 2023; 15 (2):e35175.
• Debnath J, Gammoh N, Ryan. Autophagy and autophagy-related pathways in cancer. Nature Reviews Molecular Cell Biology 2023; 24(8), 560–75.
• Nakkas H, Ocal B, Kipel S, Akcan G, Sahin C, Ardicoglu, A, Cayli S. Ubiquitin proteasome system and autophagy associated proteins in human testicular tumors. Tissue and Cell 2021; 71, 101513.
• Mao J, Zigo M, Zuidema D, Sutovsky M, Sutovsky P. NEDD4-like ubiquitin ligase 2 protein (NEDL2) in porcine spermatozoa, oocytes, and preimplantation embryos and its role in oocyte fertilization. Biology of Reproduction 2021; 104(1), 117–29.
• Wallenberg K, Wallenberg A. The expression of ATG4 in testes. The Human Protein Atlas. 2005. Available at: https://www.proteinatlas.org/ENSG00000101844 ATG4A/tissue/testis.