Ahmet İYİBOZKURT, Bedia ÇAKMAKOĞLU, Baris ERTUGRUL, Elif Sinem İPLİK

NF-қB and COX-2 Relation Between Endometrial Cancer and the Clinicopathological Parameters

Objective: Our study examines nuclear factor kappa B (NF-қB) and cyclooxygenase-2 (COX-2) polymorphisms in the most common gynecological cancer type, endometrial cancer, and the relationship between disease parameters and these polymorphisms. Methods: In our patient group; while 109 endometrial cancer patients were examined and treated in the Department of Gynecology and Obstetrics, Istanbul Medical Faculty, and 106 healthy women without the disease were included in the control group. DNA of blood samples taken from all groups were isolated; COX-2 765C> G and COX-2 1195A> G polymorphisms were studied with NF-қB-94 ins / delATTG. Genotypes analyzed using the PCR-based restriction fragment length polymorphisms (RFLP) method were investigated in terms of the relationship between endometrial cancer susceptibility and endometrial cancer disease parameters. Results in SPSS 17 program; Student’s t-tests were analyzed using Anova, Fisher’s exact, and Chi-square tests. Results: NF-қB D + and DD genotype, COX-2 765 G + and GG genotype, and COX-2 1195 AA genotype were found to be significantly more common in the endometrial cancer group compared to the control group (p

Keywords:

COX endometrial cancer, genotype, NF-қB, polymorphism,

PDF

___

[1] Gultekin M, Kucukyildiz I, Karaca MZ, Dundar S, Boztas G, Turan SH, Hacikamiloglu E, Keskinkilic B. Trends of gynecological cancers in Turkey: Toward Europe or Asia? Int J Gynecol Cancer. 2017; 27 (7): 1525-1533. DOI: 10.1097/ IGC.000.000.0000001026.
[2] Hall M, Peters G. Genetic alterations of cyclins, cyclindependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res 1996;68:67–108. DOI: 10.1016/s0065- 230x(08)60352-8.
[3] Prat J, Oliva E, Lerma E, Matias-Guiu X. Uterine papillary serous adenocarcinoma. A 10-case study of p53 and c-erbB-2 expression and DNA content. Cancer 1994;74 (16):1778–1783.
[4] Feldman I, Feldman GM, Mobarak C, Dunkelberg JC, Leslie KK. Identification of proteins within the nuclear factor-kappa B transcriptional complex including estrogen receptor-alpha. Am J Obstet Gynecol. 2007;196(4):394.e1-11; discussion 394. e11-3. DOI: 10.1016/j.ajog.2006.12.033.
[5] Modugno F, Ness RB, Chen C, Weiss NS. Inflammation and endometrial cancer: A hypothesis. Cancer Epidemiol Biomarkers Prev 2005;14 (12):2840–2847. DOI: 10.1158/1055- 9965.EPI-05-0493.
[6] Pallares J, Martínez-Guitarte JL, Dolcet X, Llobet D, Rue M, Palacios J, Prat J, Matias-Guiu X. Abnormalities in the NFkappaB family and related proteins in endometrial carcinoma. J Pathol. 2004;204(5):569-577. DOI: 10.1002/path.1666.
[7] Oh JH, Kim JH, Ahn HJ, Yoon JH, Yoo SC, Choi DS, Lee IS, Ryu HS, Min CK. Syndecan-1 enhances the endometrial cancer invasion by modulating matrix metalloproteinase-9 expression through nuclear factor kappaB. Gynecol Oncol. 2009;114(3):509-515. DOI: 10.1016/j.ygyno.2009.05.027.
[8] Tong BJ, Tan J, Tajeda L, Das SK, Chapman JA, DuBois RN, Dey SK. Heightened expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-delta in human endometrial adenocarcinoma. Neoplasia. 2000; 2(6): 483-490. DOI: 10.1038/sj.neo.7900119.
[9] Lambropoulou M, Alexiadis G, Limberis V, Nikolettos N, Tripsianis G. Clinicopathologic and prognostic significance of cyclooxygenase-2 expression in endometrial carcinoma. Histol Histopathol. 2005;20(3):753-759. DOI: 10.14670/HH-20.753.
[10] Lambropoulou M, Papadopoulos N, Tripsianis G, Alexiadis G, Pagonopoulou O, Kiziridou A, Liberis V, Kakolyris S, Chatzaki E. Co-expression of survivin, c-erbB2, and cyclooxygenase-2 (COX-2): prognostic value and survival of endometrial cancer patients. J Cancer Res Clin Oncol. 2010; 136 (3): 427-435. DOI: 10.1007/s00432.009.0673-6.
[11] St-Germain ME, Gagnon V, Parent S, Asselin E. Regulation of COX-2 protein expression by Akt in endometrial cancer cells is mediated through NF-kappaB/IkappaB pathway. Mol Cancer. 2004 11;3:7. DOI: 10.1186/1476-4598-3-7.
[12] Domenyuk VP, Litovkin KV, Verbitskaya TG, Dubinina VG, Bubnov VV. Identification of new DNA markers of endometrial cancer in patients from the Ukrainian population. Exp Oncol. 2007;29(2):152-155.
[13] Gonzalez-Ramos R, Defrere S, Devoto L. Nuclear factorkappaB: A main regulator of inflammation and cell survival in endometriosis pathophysiology. Fertil Steril. 2012;98(3):520- 528. DOI: 10.1016/j.fertnstert.2012.06.021.
[14] Elwood PC, Gallagher AM, Duthie GG, Mur LA, Morgan G. Aspirin, salicylates, and cancer. Lancet 2009;373 (9671) :1301- 1309. DOI: 10.1016/S0140-6736(09)60243-9.
[15] Andersen V, Christensen J, Overvad K, Tjonneland A, Vogel U. Polymorphisms in NF-қB, PXR, LXR and risk of colorectal cancer in a prospective study of Danes. BMC Cancer 2010;10:484. DOI: 10.1186/1471-2407-10-484.
[16] Vaskivuo TE, Stenback F, Tapanainen JS. Apoptosis and apoptosis related factors Bcl-2, Bax, Tumor necrosis factor alfa, and NF-kB in human endometrial hyperplasia and carcinoma. Cancer 2002;95(7):1463-1471. DOI: 10.1002/cncr.10876.
[17] de Martin R, Schmid JA, Hofer-Warbinek R. The NF-kappaB/rel family of transcription factors in oncogenic transformation and apoptosis. Mutat Res 1999;437 (3): 231-243. DOI: 10.1016/ s1383-5742(99)00089-7.
[18] Nagata S. Apoptosis by death factor. Cell 1997;8 (3)8 :355-365. DOI: 10.1016/s0092-8674(00)81874-7.
[19] Kalkoven E, Wissink S, van der Saag PT, van der BB. Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor. J Biol Chem. 1996;271(11): 6217- 6224. DOI: 10.1074/jbc.271.11.6217.
[20] Higgins KA, Perez JR, Coleman TA, Dorshkind K, McComas WA, Sarmiento UM, Rosen CA, Narayanan R. Antisense inhibition of the p65 subunit of NF-kappa B blocks tumorigenicity and causes tumor regression. Proc Natl Acad Sci U S A. 1993; 1;90(21):9901-9905. DOI: 10.1073/pnas.90.21.9901.
[21] Tang Z, Nie ZL, Pan Y, Zhang L, Gao L, Zhang Q, Lili Qu, Bangshun He, Song G, Zhang Y and Wang S. The Cox-2 1195G>A polymorphism and cancer risk: A meta-analysis of 25 case-control studies. Mutagenesis 2011;26(6):729-734. DOI: 10.1093/mutage/ger040.
[22] Hoff JH, te Morsche RHM, Roelofs HMJ, van der Logt EMJ, Nagengast FM, Peters WHM. COX-2 polymorphisms 765G>C and 1195A>G and colorectal cancer risk. World J Gastroenterol 2009;15(36):4561-4565. DOI: 10.3748/wjg.15.4561.
[23] Zhang X, Miao X, Tan W, Ning B, Liu Z, Hong Y, Song W, Guo Y, Zhang X, Shen Y, Qiang B, Kadlubar FF, Lin D. Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology 2005;129 (2):565-576. DOI: 10.1016/j.gastro.2005.05.003.
[24] Fujiwaki R, Iida K, Kanasaki H, Ozaki T, Hata K, Miyazaki K. Cyclooxygenase-2 expression in endometrial cancer: correlation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase. Hum Pathol. 2002;33(2):213-219. DOI: 10.1053/hupa.2002.31292.
[25] Liang JT, Huang KC, Jeng YM, Lee PH, Lai HS, Hsu HC. Microvessel density, cyclooxygenase 2 expression, K-ras muıtation and p53 overexpression in colonic cancer. Br J Surg 2004;91(3):355- 361. DOI: 10.1002/bjs.4447.
[26] Yoshimatsu K, Golijanin D, Paty PB, Soslow RA, Jakobsson PJ, DeLellis RA, Subbaramaiah K, Dannenberg AJ. Inducible microsomal prostaglandin E synthase is overexpressed in colorectal adenomas and cancer. Clin Cancer Res. 2001; 7(12):3971-3976.
[27] Ma X, Hui Y, Lin L, Wu Y, Zhang X, Liu P. Clinical significance of COX-2, GLUT-1 and VEGF expressions in endometrial cancer tissues. Pak J Med Sci. 2015;31(2):280-284. DOI: 10.12669/ pjms.312.6604.
[28] Lupi LA, Cucielo MS, Silveira HS, Gaiotte LB, Cesário RC, Seiva FRF, de Almeida Chuffa LG. The role of Toll-like receptor 4 signaling pathway in ovarian, cervical, and endometrial cancers. Life Sci. 2020;15; 247:117435 DOI:10.1016/j. lfs.2020.117435.
[29] Cavalcanti V, Ponce TG, Mafra FA, André GM, Christofolini DM, Barbosa CP, Bianco B. Evaluation of the frequency of G-765C polymorphism in the promoter region of the COX-2 gene and its correlation with the expression of this gene in the endometrium of women with endometriosis. Arch Gynecol Obstet. 2016;293(1):109-115. DOI: 10.1007/s00404.015.3808-9