https://doi.org/10.4081/aiua.2021.2.148

Gas6 expression and Tyrosine kinase Axl Sky receptors: Their relation with tumor stage and grade in patients with bladder cancer

Vol. 93 No. 2 (2021)
Submitted: March 31, 2021
Accepted: May 17, 2021
Published: June 28, 2021
Bladder cancer, Gas6, Axl, Sky, Tyro3
Abstract Views: 1324
PDF: 606
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

Murat Akgül
drmuratakgul@gmail.com
Department of Urology, Tekirdag Namık Kemal University Medical School, Tekirdag, Turkey.
Özgür Baykan
Department of Biochemistry, Balıkesir University Medical School, Balıkesir, Turkey.
Zeynep Çağman
Department of Biochemistry, Bezmialem University, School of Pharmacy, Istanbul, Turkey.
Mustafa Özyürek
Department of Physiology, Marmara University, School of Medicine, Istanbul, Turkey.
İlker Tinay
Anadolu Medical Center, Gebze, Kocaeli, Turkey.
Cem Akbal
Department of Urology, Acıbadem University, School of Medicine, Istanbul, Turkey.
Fikriye Uras
Department of Biochemistry, Marmara University, School of Pharmacy, Istanbul, Turkey.
Levent Türkeri
Department of Urology, Acıbadem University, School of Medicine, Istanbul, Turkey.

Objectives: It has been shown that the dysregulation of tyrosine kinase Axl receptor and its ligand growth arrest-specific gene (Gas6) are associated with poor prognosis in various types of tumors but there is not enough study about their importance in bladder cancer (BC). We evaluated the relation of Gas6 gene expression and tyrosine- kinase Axl and Sky (Tyro 3) receptors with tumor stage and grade in patients with BC.
Material and Methods: The study group consists of 55 patients whose transurethral resection of bladder (TUR-B) has been performed due to BC and the control group consists of 12 patients with normal bladder mucosa. In tissues mRNAs of Gas6, Axl, and Sky receptors were examined by quantitative (Real-Time) PCR (qPCR). Protein expression was measured by immunohistochemistry. Plasma Gas6 protein levels were compared with control group by ELISA method.
Results: Patients with BC were grouped as Ta low (n=17), Ta high (n=5), T1 low (n=9), T1 high (n=8) and T2 (n=16) according to their TUR-B pathologies. The qPCR analysis showed that the expression of Gas6 gene and Axl receptor is higher in the tumor-positive group and the immune-histochemical showed that the bladder samples of the tumor-positive group stained significantly positive. When the patients are grouped according to the TUR-B pathologies, a statistical significant difference was observed among groups in the qPCR analysis ratios of Gas6 gene and Axl receptor by (p < 0.05) but no significance was found for Sky receptor (p > 0.05). When Gas6 protein levels in plasma samples were compared by ELISA method, a statistical significance was determined among groups (p = 0.001).
Conclusions: Our findings indicate that mRNAs of Gas6 and Axl receptor are closely related to tumor stage and grade in patients with BC. Further studies are needed for understanding the role of Gas6 and its receptors on the neoplastic transformation in terms of novel biomarkers and potential therapeutic targets.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

Citations

Crossref
Scopus
Google Scholar
Europe PMC
Antoni S, Ferlay J, Soerjomataram I, et al. Bladder cancer incidence and mortality: A global overview and recent trends. Eur Urol. 2017; 71:96. DOI: https://doi.org/10.1016/j.eururo.2016.06.010
Kates M, Bivalacqua TJ. Non-muscle invasive bladder cancer. Campell-Walsh Urology 12th edition Elsevier Saunders Press 2020; 135:14115.
Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene 2000; 19:5548-57. DOI: https://doi.org/10.1038/sj.onc.1203957
Hafizi S, Dahlbäck B. Gas6 and protein S. The FEBS Journal. 2006; 273:5231 44. DOI: https://doi.org/10.1111/j.1742-4658.2006.05529.x
Brown M, Black JR, Sharma R, et al. Gene of the month:Axl. J Clin Path. 2016; 69:391. DOI: https://doi.org/10.1136/jclinpath-2016-203629
Paccez JD, Vogelsang M, Parker MI, et al. The receptor tyrosine kinase Axl in cancer: biological functions and therapeutic implications. Int J Cancer. 2014; 134:1024. DOI: https://doi.org/10.1002/ijc.28246
Wu G, Ma Z, Cheng Y, et al. Targeting Gas6 / TAM in cancer cells and tumor microenvironment. Mol Cancer. 2018; 17:20. DOI: https://doi.org/10.1186/s12943-018-0769-1
Yeh CY, Shin SM, Yeh HH, et al. Transcriptional activation of the Axl and PDGFR-a by c-Met through a ras-and Src-independent mechanism in human bladder cancer. BMC cancer. 2011; 11:139. DOI: https://doi.org/10.1186/1471-2407-11-139
Rui X, Wang L, Pan H, et al. Lnc RNA GAS6-AS 2 promotes bladder cancer proliferation and metastasis via GAS6-AS 2/miR-298/CDK 9 axis. J Cell Mol Med. 2019; 23:865-876. DOI: https://doi.org/10.1111/jcmm.13986
Cagman Z, Bingol Ozakpinar O, Cirakli Z, et al. Reference intervals for growth arrest-specific 6 protein in adults. Scand J Clin Lab Invest. 2017;77:109-114. DOI: https://doi.org/10.1080/00365513.2016.1275768
Babjuk M, Burger M, Comperat E, et al. European Association of Urology on non muscle invasive bladder cancer. EAU Guidelines. 2020; 4:8.
Eksi Alp E, Altinkaya N, Cagman Z, et al. Plasma growth arrest-specific 6 levels in term and preterm newborns. J Mat-Fet Neo Med. 2018; 31:1151. DOI: https://doi.org/10.1080/14767058.2017.1311311
Uras F, Küçük B, Özakpınar ÖB, et al. Growth Arrest-Specific 6 (Gas6) and TAM receptors in mouse platelets. Turk J Hemat. 2015; 32:58. DOI: https://doi.org/10.4274/tjh.2013.0097
Lopez SM, Hodgson MC, Packianathan C, et al. Determinants of the tumor suppressor INPP4B protein and lipid phosphatase activities. Bioch Biophy Res Comm. 2013; 440:277. DOI: https://doi.org/10.1016/j.bbrc.2013.09.077
Zhang S, Xu XS, Yang JX, et al. The prognostic role of Gas6 / Axl axis in solid malignancies: a meta-analysis and literature review. Oncotargets and Therapy. 2018; 11:509. DOI: https://doi.org/10.2147/OTT.S150952
Rankin E, Giaccia A. The receptor tyrosine kinase AXL in cancer progression. Cancers. 2016; 8:103. DOI: https://doi.org/10.3390/cancers8110103
Gustafsson A, Martuszewska D, Johansson M, et al. Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival. Clin Cancer Res. 2009; 15:4742. DOI: https://doi.org/10.1158/1078-0432.CCR-08-2514
Sauter G, Algaba F, Amin M, et al. Tumors of the urinary system: non-invasive urothelial neoplasias. In: Eble JN, Sauter G, Epstein Jl, Sesterhenn I, eds. WHO classification of classification of tumors of the urinary system and male genital organs. Lyon: IARCC Press 2004; 29.
Sun WS, Fujimoto J, Tamaya T. Coexpression of growth arrestspecific gene 6 and receptor tyrosine kinases Axl and Sky in human uterine endometrial cancers. Ann of Onco. 2003; 14:898. DOI: https://doi.org/10.1093/annonc/mdg257
Hattori S, Kikuchi E, Kosaka T, et al. Relationship between increased expression of the Axl/Gas6 signal cascade and prognosis of patients with upper tract urothelial carcinoma. Ann Surg Oncol. 2016; 23:663. DOI: https://doi.org/10.1245/s10434-015-4848-x
Wu X, Liu X, Koul S, et al. AXL kinase as a novel target for cancer therapy. Oncotarget. 2014; 5:9546. DOI: https://doi.org/10.18632/oncotarget.2542
Holland SJ, Pan A, Franci C, et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Canc Res. 2010; 70:1544. DOI: https://doi.org/10.1158/0008-5472.CAN-09-2997
Wang X, Saso H, Iwamoto T, et al. TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase. Cancer Res. 2013; 73:6516. DOI: https://doi.org/10.1158/0008-5472.CAN-13-0967
Mao S, Wu Y, Wang R, et al. Overexpression of GAS6 promotes cell proliferation and invasion in bladder cancer by activation of the PI3K/AKT pathway. Onco Targets Ther. 2020; 13:4813-24. DOI: https://doi.org/10.2147/OTT.S237174
Ekman C, Stenhoff J, Dahlback B. Gas6 is complexed to the soluble tyrosine kinase receptor Axl in human blood. J Thromb Haemost. 2010; 8:838. DOI: https://doi.org/10.1111/j.1538-7836.2010.03752.x

Supporting Agencies

This investigation was supported by Marmara University Scientific Research Projects Committee.

How to Cite

Akgül, M., Baykan, Özgür, Çağman , Z., Özyürek , M. ., Tinay, İlker, Akbal , C. ., Uras , F. ., & Türkeri , L. . (2021). Gas6 expression and Tyrosine kinase Axl Sky receptors: Their relation with tumor stage and grade in patients with bladder cancer. Archivio Italiano Di Urologia E Andrologia, 93(2), 148–152. https://doi.org/10.4081/aiua.2021.2.148

PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.