Human papillomavirus (HPV) infection is necessary but not a sufficient cause for the development of invasive cervical cancer (ICC). Epithelial tissues, target for HPV, are exposed to reactive oxygen species (ROS) associated with tumor initiation and progression. The NADPH oxidase (NOX) and catalase (CAT) are involved in hydrogen peroxide (H2O2) production and inactivation, respectively. P22phox is the NOX subunit encoded by the CYBA gene that has a functional polymorphism (C-242T). This protein is involved in the regulation of electron transfer to oxygen. CAT is a hemic enzyme that plays a role in regulating H2O2 concentration, with a functional polymorphism (C-262T) in its gene. We evaluated CYBA C-242T and CAT C262T genetic polymorphisms and their interaction in 132 women with ICC. We found that CYBA C-242T and CAT C262T genotype frequencies were significantly different between ICC and controls (χ 2 test, p = 0.017 and p = 0.009, respectively). Women with the C/T CYBA-242 genotype had a lower risk for ICC development (odds ratio (OR) = 0.515, 95 % confidence interval (CI) 0.291–0.914, p = 0.023) whereas T/T CAT-262 genotype carriers present an increased risk for ICC (OR = 3.034, 95 % CI 1.462–6.298, p = 0.003). Women with C/C genotype for CYBA and T/T genotype for CAT had an increased risk to develop ICC comparing with the interaction of the other possible genotypes of both genes (OR = 3.952, 95 % CI 1.075–14.521, p = 0.032). The CYBA C-242T and CAT C-262T genetic polymorphisms and their epistatic interactions can be associated with ICC through mechanisms related with the role of ROS in cell proliferation and apoptosis.
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Muñoz N, Castellsagué X, de González AB, Gissmann L. Chapter 1: HPV in the etiology of human cancer. Vaccine. 2006;31(24 Suppl 3):S3/1–10.
De Marco F. Oxidative stress and HPV carcinogenesis. Viruses. 2013;5(2):708–31.
Wu W-S. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev. 2006;25(4):695–705.
Laurent A, Nicco C, Chéreau C, Goulvestre C, Alexandre J, Alves A, et al. Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res. 2005;65(3):948–56.
Bechtel W, Bauer G. Catalase protects tumor cells from apoptosis induction by intercellular ROS signaling. Anticancer Res. 2009;29(11):4541–57.
Bechtel W, Bauer G. Modulation of intercellular ROS signaling of human tumor cells. Anticancer Res. 2009;29(11):4559–70.
Bauer G. Targeting extracellular ROS signaling of tumor cells. Anticancer Res. 2014;34(4):1467–82.
Lambeth JD. Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic Biol Med. 2007;43(3):332–47.
Sardina JL, López-Ruano G, Sánchez-Abarca LI, Pérez-Simón JA, Gaztelumendi A, Trigueros C, et al. p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation. Cell Death Differ. 2010;17(12):1842–54.
Ushio-fukai M, Zafari AM, Fukui T, Ishizaka N, Griendling KK. p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells*. J Biol Chem. 1996;271(38):23317–21.
Najafi M, Alipoor B, Shabani M, Amirfarhangi A, Ghasemi H. Association between rs4673 (C/T) and rs13306294 (A/G) haplotypes of NAD(P)H oxidase p22phox gene and severity of stenosis in coronary arteries. Gene. 2012;499(1):213–7.
Schreiber R, Ferreira-Sae MC, Ronchi J A, Pio-Magalhães J A, Cipolli J A, Matos-Souza JR, et al. The C242T polymorphism of the p22-phox gene (CYBA) is associated with higher left ventricular mass in Brazilian hypertensive patients. BMC Med Genet. BioMed Central Ltd; 2011;12(1):114.
Chang D, Hu ZL, Zhang L, Zhao YS, Meng QH, Guan QB, et al. Association of catalase genotype with oxidative stress in the predication of colorectal cancer: modification by epidemiological factors. Biomed Environ Sci. 2012;25(2):156–62.
Chelikani P, Ramana T, Radhakrishnan TM. Catalase: a repertoire of unusual features. Indian J Clin Biochem. 2005;20(2):131–5.
Khodayari S, Salehi Z, Asl SF, Aminian K, Mirzaei Gisomi N, Dalivandan ST. Catalase gene C-262T polymorphism: importance in ulcerative colitis. J Gastroenterol Hepatol. 2013;28(5):819–22.
Matos A, Moutinho J, Pinto D, Medeiros R. The influence of smoking and other cofactors on the time to onset to cervical cancer in a southern European population. Eur J Cancer Prev. 2005;14(5):485–91.
Lahiri DK, Nurnberger JI. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991;19(19):5444.
Mesquita FS, Dyer SN, Heinrich DA, Bulun SE, Marsh EE, Nowak RA. Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells. Biol Reprod. 2010;82(2):341–51.
Manda G, Nechifor MT, Neagu T-M. Reactive oxygen species, cancer and anti-cancer therapies. Curr Chem Biol [Internet]. 2009;3(1):342–66.
Behrend L, Henderson G, Zwacka R. Molecular mechanisms of signalling molecular mechanisms of signalling transformation. Biochem Soc Trans. 2003;31(6):1441–4.
Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat. 2004;7(2):97–110.
Guzik TJ, West NEJ, Black E, McDonald D, Ratnatunga C, Pillai R, et al. Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis. 2000;102(15):1744–7.
Wu Z, Lou Y, Jin W, Liu Y, Lu L, Chen Q, et al. Relationship of the p22phox (CYBA) gene polymorphism C242T with risk of coronary artery disease: a meta-analysis. PLoS One. 2013;8(9):e70885.
Comings DE, MacMurray JP. Molecular heterosis: a review. Mol Genet Metab. 2000;71(1–2):19–31.
Fabre E, Raynaud-Simon A, Golmard J, Hebert M, Dulcire X, Succari M, et al. Gene polymorphisms of oxidative stress enzymes: prediction of elderly renutrition. Am J Clin Nutr. 2008;4:1504–12.
Funke S, Risch A, Nieters A, Hoffmeister M, Stegmaier C, Seiler CM, et al. Genetic polymorphisms in genes related to oxidative stress (GSTP1, GSTM1, GSTT1, CAT, MnSOD, MPO, eNOS) and survival of rectal cancer patients after radiotherapy. J Cancer Epidemiol. 2009;2009:302047.
The authors would like to thank the Instituto de Investigação Científica Bento da Rocha Cabral for financial support regarding the determination of C-242T CYBA and C-262T CAT genetic polymorphisms.
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Castaldo, S.A., da Silva, A.P., Matos, A. et al. The role of CYBA (p22phox) and catalase genetic polymorphisms and their possible epistatic interaction in cervical cancer. Tumor Biol. 36, 909–914 (2015). https://doi.org/10.1007/s13277-014-2714-2
- Oxidative stress
- Cervical cancer
- CYBA (p22phox)