Middle East Journal of Cancer

Prostaglandin Synthase 2/Cyclooxygenase 2 Gene Polymorphisms and Susceptibility to Urothelial Bladder Cancer in an Iranian Population

Document Type : Original Article(s)

Authors

Kamyar Mansori 1
Mohammad Reza Nowroozi 2
Amirreza Farzin 2
Solmaz Ohadian Moghadam 2

1 Department of Epidemiology and Biostatistics, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

2 Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran

https://doi.org/10.30476/mejc.2021.88204.1463
Abstract
Background: Prostaglandin-endoperoxide synthase 2, recognized as cyclooxygenase 2 (COX-2), is an important enzyme contributing to the generation of proinflammatory prostaglandins. It can play a role in increased tumor angiogenesis, apoptosis inhibition, metastasis, and invasion of tumors. Single nucleotide polymorphisms (SNPs) of the COX-2 promoter may associate with the cancer predisposition. In the present work, we aimed to explore whether SNPs of COX-2 gene affect both the risk of development and grade of bladder cancer.
Method: This case-control study was performed and the genetic polymorphisms of six COX-2 SNPs including, intron 1 (rs2745557), intron 5 (rs16825748), intron 6 (rs2066826), T+8473C (rs5275), G-765 (rs20417), and A-1195G (rs68946) were genotyped in 80 healthy controls and 80 bladder cancer patients using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). To select independent prognostic factors, the univariate and multivariate analyses were implemented.
Results: Univariate logistic regression model indicated a significant association between COX-2 765G>C heterozygous GC genotype and greater risk of bladder cancer (OR: 2.07; 95% CI: 1.03 - 4.15; P = 0.04). However, the multivariate logistic regression analysis showed no associations between COX-2 variants and bladder cancer development.
Conclusion: We concluded that COX-2 polymorphisms do not contribute to the genetic susceptibility to urothelial bladder cancer in an Iranian population. However, the only genotype in which the frequency of alleles significantly differed between the two groups of high-grade tumors and low-grade tumors was COX-2 8473T> C (rs5275). Moreover, our findings showed that both smoking and family history of cancer play a role in susceptibility to bladder cancer.

Keywords

Urinary bladder neoplasms
Polymorphism
Single nucleotide
Cyclooxygenase 2
Case-control studies
Restriction fragment length polymorphisms

How to cite this article:

Mansori K, Nowroozi MR, Farzin A, Ohadian Moghadam S. Prostaglandin synthase 2/cyclooxygenase 2 gene polymorphisms and susceptibility to urothelial bladder cancer in an Iranian population. Middle East J Cancer. 2022;13(3):418-26 doi: 10.30476/mejc.2021.88204.1463.

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. doi: 10.3322/caac.21442.
  2. Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: A global overview and recent trends. Eur Urol. 2017;71(1):96-108. doi: 10.1016/j.eururo.2016.06.010.
  3. Rafiemanesh H, Lotfi Z, Bakhtazad S, Ghoncheh M, Salehiniya H. The epidemiological and histological trend of bladder cancer in Iran. J Cancer Res Ther. 2018;14(3):532-6. doi: 10.4103/0973-1482.172134.
  4. Wan GX, Chen P, Yu XJ, Di QS, Yu YD, Lei JH, et al. Cyclooxygenase-2 polymorphisms and bladder cancer risk: a meta-analysis based on case-control studies. Int J Clin Exp Med. 2015;8(3):3935-45.
  5. Lin J, Spitz MR, Dinney CP, Etzel CJ, Grossman HB, Wu X. Bladder cancer risk as modified by family history and smoking. Cancer. 2006;107(4):705-11.
  6. Wu X, Gu J, Grossman HB, Amos CI, Etzel C, Huang M, et al. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am J Hum Genet. 2006;78(3):464-79. doi: 10.1086/500848.
  7. Gangwar R, Mandhani A, Mittal RD. Functional polymorphisms of cyclooxygenase-2 (COX-2) gene and risk for urinary bladder cancer in North India. Surgery. 2011;149(1):126-34.
  8. Chang WS, Yang MD, Tsai CW, Cheng LH, Jeng LB, Lo WC, et al. Association of cyclooxygenase 2 single-nucleotide polymorphisms and hepatocellular carcinoma in Taiwan. Chin J Physiol. 2012;55(1):1-7. doi: 10.4077/CJP.2012.AMM056.
  9. Pereira C, Sousa H, Ferreira P, Fragoso M, Moreira-Dias L, Lopes C, et al. -765G > C COX-2 polymorphism may be a susceptibility marker for gastric adenocarcinoma in patients with atrophy or intestinal metaplasia. World J Gastroenterol. 2006;12(34):5473-8. doi: 10.3748/wjg.v12.i34.5473.
  10. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries SE, et al. Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol. 2002;22(10):1631-6. doi: 10.1161/01.atv.0000030340.80207.c5.
  11. Cheng I, Liu X, Plummer SJ, Krumroy LM, Casey G, Witte JS. COX2 genetic variation, NSAIDs, and advanced prostate cancer risk. Br J Cancer. 2007;97(4):557-61. doi: 10.1038/sj.bjc.6603874.
  12. Mittal M, Kapoor V, Mohanti BK, Das SN. Functional variants of COX-2 and risk of tobacco-related oral squamous cell carcinoma in high-risk Asian Indians. Oral Oncol. 2010;46(8):622-6. doi: 10.1016/j.oraloncology.2010.06.002.
  13. Wang W, Fan X, Zhang Y, Yang Y, Yang S, Li G. Association between COX-2 polymorphisms and lung cancer risk. Med Sci Monit. 2015;21:3740-7. doi: 10.12659/msm.894839.
  14. Tomitão MTP, Nahas SC, Kubrusly MS, Furuya TK, Diniz MA, Marie SKN, et al. Cyclooxygenase-2 gene polymorphisms and susceptibility to colorectal cancer in a Brazilian population. J Gastrointest Oncol. 2017;8(4):629-635. doi: 10.21037/jgo.2017.03.05.
  15. Luo MX, Long BB, Li F, Zhang C, Pan MT, Huang YQ, et al. Roles of Cyclooxygenase-2 gene -765G > C (rs20417) and -1195G > A (rs689466) polymorphisms in gastric cancer: A systematic review and meta-analysis. Gene. 2019;685:125-35. doi: 10.1016/j.gene.2018.10.077.
  16. Zhang X, Miao X, Tan W, Ning B, Liu Z, Hong Y, et al. Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology. 2005;129(2):565-76. doi: 10.1016/j.gastro.2005.05.003.
  17. Tan W, Wu J, Zhang X, Guo Y, Liu J, Sun T, et al. Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer. Carcinogenesis. 2007;28(6):1197-201. doi: 10.1093/carcin/bgl242.
  18. Liu L, Zhou F, Ren S, Chen X, Li X, Li W, et al. Prognostic value of cyclooxygenase-2 gene polymorphisms in advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy. Asia Pac J Clin Oncol. 2016;12(2):e339-46. doi: 10.1111/ajco.12258.
  19. Ben Nasr H, Chahed K, Bouaouina N, Chouchane L. PTGS2 (COX-2) -765 G > C functional promoter polymorphism and its association with risk and lymph node metastasis in nasopharyngeal carcinoma. Mol Biol Rep. 2009;36(1):193-200. doi: 10.1007/s11033-007-9166-3.
  20. Chang WS, Tsai CW, Ji HX, Wu HC, Chang YT, Lien CS, t al. Associations of cyclooxygenase 2 polymorphic genotypes with bladder cancer risk in Taiwan. Anticancer Res. 2013;33(12):5401-5.
  21. Koh WP, Yuan JM, van den Berg D, Lee HP, Yu MC. Interaction between cyclooxygenase-2 gene polymorphism and dietary n-6 polyunsaturated fatty acids on colon cancer risk: the Singapore Chinese Health Study. Br J Cancer. 2004;90(9):1760-4. doi: 10.1038/sj.bjc.6601797.
  22. Li Q, Ma C, Zhang Z, Chen S, Zhi W, Zhang L, et al. Association between cyclooxygenase-2 (COX-2) 8473 T > C polymorphism and cancer risk: a meta-analysis and trial sequential analysis. BMC Cancer. 2018;18(1):847. doi: 10.1186/s12885-018-4753-3.
  23. Campa D, Zienolddiny S, Maggini V, Skaug V, Haugen A, Canzian F. Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis. 2004;25(2):229-35.
  24. Gao J, Ke Q, Ma HX, Wang Y, Zhou Y, Hu ZB, et al. Functional polymorphisms in the cyclooxygenase 2 (COX-2) gene and risk of breast cancer in a Chinese population. J Toxicol Environ Health A. 2007;70(11):908-15. doi: 10.1080/15287390701289966.
  25. Langsenlehner U, Yazdani-Biuki B, Eder T, Renner W, Wascher TC, Paulweber B, et al. The cyclooxygenase-2 (PTGS2) 8473T>C polymorphism is associated with breast cancer risk. Clin Cancer Res. 2006;12(4):1392-4. doi: 10.1158/1078-0432.CCR-05-2055.
  26. Cox DG, Pontes C, Guino E, Navarro M, Osorio A, Canzian F, et al. Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer. Br J Cancer. 2004;91(2):339-43. doi: 10.1038/sj.bjc.6601906.
  27. Sørensen M, Autrup H, Tjønneland A, Overvad K, Raaschou-Nielsen O. A genetic polymorphism in prostaglandin synthase 2 (8473, T-->C) and the risk of lung cancer. Cancer Lett. 2005;226(1):49-54. doi: 10.1016/j.canlet.2005.03.037.
  28. Murta-Nascimento C, Silverman DT, Kogevinas M, García-Closas M, Rothman N, Tardón A, et al. Risk of bladder cancer associated with family history of cancer: do low-penetrance polymorphisms account for the increase in risk? Cancer Epidemiol Biomarkers Prev. 2007;16(8):1595-600. doi: 10.1158/1055-9965.EPI-06-0743.

 

Home

Guide for Authors

Submit Manuscript

Guide for Reviewers

Contact Us