Original Article
 

Molecular Characteristics of Bladder Tumor: Increased Gene Expression of MAGE-A6 and MAGE-A11 with Decreased MicroRNA-34a and MicroRNA-125b

Abstract

Bladder cancer is recognized as one of the top ten most common cancers worldwide. Activation of oncogenes, inactivation of tumor suppressor genes, and dysregulation of androgen signaling pathways are three major pathophysiological causes in the development of bladder tumors. Discovering potential biomarkers is required for the management and immunotherapy of bladder cancer. Melanoma-associated antigen (MAGE)-A6 and MAGE-A11 are two cancer-testis antigens that are potential coregulators of androgen receptors. MicroRNAs, especially miR-34a and miR-125b are two important tumor suppressors that play a critical role in regulating different signaling pathways and inhibiting tumor development.
Twenty-nine surgical tissue biopsies were collected from patients with no preoperative chemotherapy or radiotherapy (26 males and, 3 females, mean age±SD: 62.4±13.3 years). Seventeen adjacent uninvolved tissues with no abnormalities upon histological examination were considered normal controls (14 males and, 3 females, mean age±SD: 64.2±7.4 years) . Quantitative PCR was performed to evaluate the gene expression level of MAGE-A6, MAGE-A11, miR-34a, and miR-125b in bladder cancer biopsies.
MAGE-A6 and MAGE-A11 expressions were significantly increased in bladder tumors compared with normal tissues. However, the expression levels of miR-34a and miR-125b were significantly downregulated in bladder tumor tissues. Interestingly, the expression level of all these genes was significantly associated with tumor grade, pathological stage (pT), and muscular invasion.
MAGE-A6 and MAGE-A11 can be considered potential markers for the diagnosis and immunotherapy of bladder tumors. Furthermore, the modulation of miR-34a and miR-125b gene expression in association with increased MAGE-A6 and MAGE-A11 genes could open a new horizon in the improvement of bladder cancer.

1. Zhu S, Yu W, Yang X, Wu C, Cheng F. Traditional Classification and Novel Subtyping Systems for Bladder Cancer. Front Oncol. 2020;10(102).
2. Saginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A. Epidemiology of Bladder Cancer. Med Sci (Basel). 2020;8(1):15.
3. Dobruch J, Daneshmand S, Fisch M, Lotan Y, Noon AP, Resnick MJ, et al. Gender and Bladder Cancer: A Collaborative Review of Etiology, Biology, and Outcomes. Eur Urol. 2016;69(2):300-10.
4. Apollo A, Ortenzi V, Scatena C, Zavaglia K, Aretini P, Lessi F, et al. Molecular characterization of low grade and high grade bladder cancer. PLOS ONE. 2019;14(1):e0210635.
5. Mhawech-Fauceglia P, Cheney RT, Schwaller J. Genetic alterations in urothelial bladder carcinoma. Cancer. 2006;106(6):1205-16.
6. Li P, Chen J, Miyamoto H. Androgen Receptor Signaling in Bladder Cancer. Cancers (Basel). 2017;9(2):20-9.
7. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86.
8. Bondhopadhyay B, Sisodiya S, Chikara A, Khan A, Tanwar P, Afroze D, et al. Cancer immunotherapy: a promising dawn in cancer research. Am J Blood Res. 2020;10(6):375-85.
9. Gjerstorff MF, Andersen MH, Ditzel HJ. Oncogenic cancer/testis antigens: prime candidates for immunotherapy. Oncotarget. 2015;6(18):15772-87.
10. Zajac P, Schultz-Thater E, Tornillo L, Sadowski C, Trella E, Mengus C, et al. MAGE-A Antigens and Cancer Immunotherapy. Front Med (Lausanne). 2017;4:18-.
11. Kerkar SP, Wang ZF, Lasota J, Park T, Patel K, Groh E, et al. MAGE-A is More Highly Expressed Than NY-ESO-1 in a Systematic Immunohistochemical Analysis of 3668 Cases. J Immunother. 2016;39(4):181-7.
12. Weon JL, Potts PR. The MAGE protein family and cancer. Curr Opin Cell Biol. 2015;37:1-8.
13. Laiseca JE, Ladelfa MF, Cotignola J, Peche LY, Pascucci FA, Castaño BA, et al. Functional interaction between co-expressed MAGE-A proteins. PLOS ONE. 2017;12(5):e0178370.
14. O'Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front Endocrinol. 2018;9(402).
15. Shah V, Shah J. Recent trends in targeting miRNAs for cancer therapy. J Pharm Pharmacol. 2020;72(12):1732-49.
16. Misso G, Zarone MR, Lombardi A, Grimaldi A, Cossu AM, Ferri C, et al. miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma. Molecular Therapy - Nucleic Acids. 2019;16:391-406.
17. Zhang L, Liao Y, Tang L. MicroRNA-34 family: a potential tumor suppressor and therapeutic candidate in cancer. J Exp Clin Cancer Res. 2019;38(1):53-8.
18. Yang G, Fu Y, Lu X, Wang M, Dong H, Li Q. miR‑34a regulates the chemosensitivity of retinoblastoma cells via modulation of MAGE‑A/p53 signaling. Int J Oncol. 2019;54(1):177-87.
19. Fernandes RC, Hickey TE, Tilley WD, Selth LA. Interplay between the androgen receptor signaling axis and microRNAs in prostate cancer. Endocr Relat Cancer. 2019;26(5):R237-r57.
20. Wong MCS, Fung FDH, Leung C, Cheung WWL, Goggins WB, Ng CF. The global epidemiology of bladder cancer: a joinpoint regression analysis of its incidence and mortality trends and projection. Sci Rep. 2018;8(1):1129.
21. Li Y, Izumi K, Miyamoto H. The role of the androgen receptor in the development and progression of bladder cancer. Jpn J Clin Oncol. 2012;42(7):569-77.
22. Boorjian S, Ugras S, Mongan NP, Gudas LJ, You X, Tickoo SK, et al. Androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancer. Urology. 2004;64(2):383-8.
23. Bar-Haim E, Paz A, Machlenkin A, Hazzan D, Tirosh B, Carmon L, et al. MAGE-A8 overexpression in transitional cell carcinoma of the bladder: identification of two tumour-associated antigen peptides. British J Cancer. 2004;91(2):398-407.
24. Otte M, Zafrakas M, Riethdorf L, Pichlmeier U, Löning T, Jänicke F, et al. MAGE-A gene expression pattern in primary breast cancer. Cancer Res. 2001;61(18):6682-7.
25. Marcar L, MacLaine NJ, Hupp TR, Meek DW. Mage-A Cancer/Testis Antigens Inhibit p53 Function by Blocking Its Interaction with Chromatin. Cancer Res. 2010;70(24):10362-70.
26. Minges JT, Su S, Grossman G, Blackwelder AJ, Pop EA, Mohler JL, et al. Melanoma antigen-A11 (MAGE-A11) enhances transcriptional activity by linking androgen receptor dimers. J Biol Chem. 2013;288(3):1939-52.
27. Karpf AR, Bai S, James SR, Mohler JL, Wilson EM. Increased expression of androgen receptor coregulator MAGE-11 in prostate cancer by DNA hypomethylation and cyclic AMP. Mol Cancer Res. 2009;7(4):523-35.
28. Macfarlane LA, Murphy PR. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2010;11(7):537-61.
29. Weeraratne SD, Amani V, Neiss A, Teider N, Scott DK, Pomeroy SL, et al. miR-34a confers chemosensitivity through modulation of MAGE-A and p53 in medulloblastoma. Neuro-Oncology. 2011;13(2):165-75.
Files
IssueVol 21 No 5 (2022) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijaai.v21i5.11043
Keywords
Bladder cancer Immunotherapy MAGE-A6 MAGE-A11 MicroRNA-34a MicroRNA-125b

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Aghamajidi A, Ousati Ashtiani Z, Mohsenzadegan M, Tajik N, Ghafoori Yazdi M, Sharifi L, Nowroozi MR. Molecular Characteristics of Bladder Tumor: Increased Gene Expression of MAGE-A6 and MAGE-A11 with Decreased MicroRNA-34a and MicroRNA-125b. Iran J Allergy Asthma Immunol. 2022;21(5):561-573.