Cyclooxygenase-2 expression in cervical cancer

Aljoša Mandić; Slavica Ušaj-Knežević; Tatjana Ivković Kapicl; Dejan Ninčić; Goran Malenković

doi:10.2298/3082

Aljoša Mandić Oncology Institute of Vojvodina, Novi Sad, Serbia
Slavica Ušaj-Knežević Oncology Institute of Vojvodina, Novi Sad, Serbia
Tatjana Ivković Kapicl Oncology Institute of Vojvodina, Novi Sad, Serbia
Dejan Ninčić Oncology Institute of Vojvodina, Novi Sad, Serbia
Goran Malenković Oncology Institute of Vojvodina, Novi Sad, Serbia

DOI: https://doi.org/10.2298/3082

Keywords: uterine cervical neoplasms, prostaglandin-endoperoxide synthases, immunohistochemistry, gene expression, sensitivity and specificity,

Abstract

Background/Aim. Cyclooxygenase (COX) or prostaglandin H2 synthase is the first enzyme that catalyzes the first two steps in the biosynthesis of prostaglandins from arachidonic acid. The aim of the study was to determine the expression level of COX-2 in patients with cervical cancer and compare it with that in the control group with no cervical pathology. Methods. The study included 76 patients divided into two groups: the control group – 30 patients without histopathological changes and the group A – 46 patients with cervical cancer, FIGO stage IB-IIA. Histopathological and immunohistochemical analyses were performed in these two groups of patients. Results. In the control group, the expression of COX-2 was not confirmed compared to the group A of 26 (56.52%) patients. The expression of COX-2 showed a statistically significant difference in the presence of lymphocytic stromal infiltration (p = 0.0053). The expression of COX-2 was more pronounced in the stromal tissue without lymphocytic infiltration (80% vs 20%). Conclusion. A higher expression of COX-2 in cervical carcinoma without stromal lymphocytic infiltration suggests a possible paradoxical effect of COX-2 in immunosuppression. Frequent COX- 2 expression in the subgroup with poor prognostic histological parameters in the group A indicates the importance of COX-2 expression in the carcinogenesis of cervical cancer.

References

Curado MP, Edwards B, Shin HR. Cancer Incidence in Five Continents. Lyon: IARC; 2007.

Pekmezović T. Cervical carcinoma: The significance of the problem. Proceedings of the Conference on Cervical Carcinoma – From the Diagnosis to Therapy. 2006 May 18−19; Geneva: ESGO Endorsed Meetings and Workshops; 2006. p. 1−3. (Serbian)

Dugandžija T, Miladinov-Mikov M. Epidemiological Characteris-tics of Cervical Cancer in Vojvodina 1993-2002. Proceeding of the International Conference on the Diagnostics and Man-agement on Breast Cancer and Cervical Cancer; Zagreb; 2006 March 6; Zagreb: Knjiga sažetaka 76; 2006.

Divvela AKC, Challa SR, Tagaram IK. Pathogenic role of Cyc-looxygenase -2 in cancer. J Healt Sci 2010; 56(5): 502−16.

Kim H, Youm H, Lee J, Min K, Chung J, Park C. Correlation be-tween cyclooxygenase-2 and tumor angiogenesis in non-small cell lung cancer. Lung Cancer 2003; 42(2): 163−70.

Sun Y, Tang XM, Half E, Kuo TM, Sinicrope FA. Cyclooxyge-nase-2 overexpression reduces apoptotic susceptibility by inhi-biting the cytochrome c-dependent apoptotic pathway in hu-man colon cancer cells. Cancer Res 2002; 62(21): 6323−8.

Maitra A, Ashfaq R, Gunn CR, Rahman A, Yeo CJ, Sohn TA, et al. Cyclooxygenase 2 expression in pancreatic adenocarcinoma andpancreatic intraepithelial neoplasia: an immunohistochemi-cal analysis with automated cellular imaging. Am J Clin Pathol 2002; 118(2): 194−201.

Liu JF, Jamieson G, Wu TC, Zhang SW, Wang QZ, Drew P. Cyc-looxygenase-2 expression in squamous cell carcinoma of the esophagus. Dis Esophagus 2006; 19(5): 350−4.

Lim HY, Joo HJ, Choi JH, Yi JW, Yang MS, Cho DY, et al. In-creased expression of cyclooxygenase-2 protein in human gas-tric carcinoma. Clin Cancer Res 2000;6(2): 519−25.

Saukkonen K, Nieminen O, Rees B, Vilkki S, Härkönen M, Juhola M, et al. Expression of cyclooxygenase-2 in dysplasia of the stomach and in intestinal-type gastric adenocarcinoma. Clin Cancer Res 2001; 7(7): 1923−31.

Shirahama T. Cyclooxygenase-2 expression is up-regulated in transitional cell carcinoma and its preneoplastic lesions in the human urinary bladder. Clin Cancer Res 2000; 6(6): 2424−30.

Shim V, Gauthier ML, Sudilovsky D, Mantei K, Chew KL, Moore DH, et al. Cyclooxygenase-2 expression is related to nuclear grade in ductal carcinoma in situ and is increased in its normal adjacent epithelium. Cancer Res 2003; 63(10): 2347−50.

Ferrandina G, Ranelletti FO, Salutari V, Gessi M, Legge F, Zannoni GF, et al. Expression of cyclooxygenase-2 (COX-2) in non-neoplastic and neoplastic vulvar epithelial lesions. Gynecol Oncol 2004; 92(2): 537−44.

Lin MT, Lee RC, Yang PC, Ho FM, Kuo ML. Cyclooxygenase-2 inducing Mcl-1-dependent survival mechanism in human lung adenocarcinoma CL1.0 cells. Involvement of phosphatidylino-sitol 3-kinase/Akt pathway. J Biol Chem 2001; 276(52): 48997−9002.

Cao Y, Pearman AT, Zimmerman GA, Mcintyre TM, Prescott SM. Intracellular unesterified arachidonic acid signals apoptosis. Proc Natl Acad Sci USA 2000; 97(21): 11280−5.

Dai Y, Zhang X, Peng Y, Wang Z. The expression of cycloox-ygenase-2, VEGF and PGs in CIN and cervical carcinoma. Gynecol Oncol 2005; 97(1): 96−103.

Mohammed SI, Knapp DW, Bostwick DG, Foster RS, Khan KN, Masferrer JL, et al. Expression of cyclooxygenase-2 (COX-2) in human invasive transitional cell carcinoma (TCC) of the uri-nary bladder. Cancer Res 1999; 59(22): 5647−50.

Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr, accessed on day/month/year.

Dixon DA. Regulation of COX-2 expression in human can-cers. In: Bertino RJ, Dannenberg AJ, du Bois RN, editors. COX-2 a new target for cancer prevention and treatment. Progress in experimental tumor research. Basel: Karger; 2003. p. 52−72.

Hartmann LC, Lingle W, Frost MH, Shaun D, Maloney RA, Vierkant V, et. al. COX-2 expression in atypia: correlation with breast cancer risk. 97th Annual Meeting. 2006 March 31- April 5; Washington, DC: American Association for Cancer Research; 2006.

Khan KN, Masferrer JL, Woerner BM, Soslow R, Koki AT. En-hanced cyclooxygenase-2 expression in sporadic and familial adenomatous polyposis of the human colon. Scand J Ga-stroenterol 2001; 36(8): 865−9.

Sudbø J, Ristimäki A, Sondresen JE, Kildal W, Boysen M, Koppang HS, et al. Cyclooxygenase-2 (COX-2) expression in high-risk premalignant oral lesions. Oral Oncol 2003; 39(5): 497−505.

Oku S, Higashi M, Imazono Y, Sueyoshi K, Enokida H, Kubo H, et al. Overexpression of cyclooxygenase-2 in high-grade human transitional cell carcinoma of the upper urinary tract. BJU Int 2003; 91(1): 109−14.

Barnes N, Haywood P, Flint P, Knox WF, Bundred NJ. Survivin expression in in situ and invasive breast cancer relates to COX-2 expression and DCIS recurrence. Br J Cancer 2006; 94(2): 253−8.

Nakopoulou L, Mylona E, Papadaki I, Kapranou A, Giannopoulou I, Markaki S, et al. Overexpression of cyclooxygenase-2 is asso-ciated with a favorable prognostic phenotype in breast carci-noma. Pathobiology 2005; 72(5): 241−9.

Nasir A, Kaiser HE, Boulware D, Hakam A, Zhao H, Yeatman T, et al. Cyclooxygenase-2 expression in right- and left-sided co-lon cancer: a rationale for optimization of cyclooxygenase-2 inhibitor therapy. Clin Colorectal Cancer 2004; 3(4): 243−7.

Soumaoro LT, Uetake H, Takagi Y, Iida S, Higuchi T, Yasuno M, et al. Co-expression of VEGF-C and COX-2 in human colo-rectal cancer and its association with lymph node metastasis. Dis Colon Rectum 2006; 49(3): 393−8.

Marrogi AJ, Travis WD, Welsh JA, Khan MA, Rahim H, Tazelaar H, et al. Nitric oxide synthase, cyclooxygenase 2, and vascular endothelial growth factor in the angiogenesis of non-small cell lung carcinoma. Clin Cancer Res 2000; 6(12): 4739−44.

Tucker ON, Dannenberg AJ, Yang EK, Zhang F, Teng L, Daly JM, et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 1999; 59(5): 987−90.

Mrena J, Wiksten JP, Thiel A, Kokkola A, Pohjola L, Lundin J, et al. Cyclooxygenase-2 Is an Independent Prognostic Factor in Gastric Cancer and Its Expression Is Regulated by the Mes-senger RNA Stability Factor HuR. Clin Cancer Res 2005; 11(20): 7362−8.

Li M, Qi S, Wang Y, Feng S, Zhang B, Wang R. Expression and clinical significance of vascular endothelial growth factor, cyc-looxygenase-2, and Bcl-2 in borderline ovarian tumors. Arch Gynecol Obstet 2005; 272(1): 48−52.

Denkert C, bel Ko ¨M, Pest S, Koch I, Berger S, Schwabe M, et al. Expression of cyclooxygenase 2 is an independent prognostic factor in human ovarian carcinoma. Am J Pathol 2002; 160(3): 893−903.

Chou Y, Chen Y, Lai C, Wang P, Yuan C. Cyclooxygenase-2 ex-pression is higher in ovarian cancer tissue adjacent to endometriosis than in ovarian cancer without comorbid endometriosis. Eur J Obstet Gynecol Reprod Biol 2006; 124(1): 101−5.

Nasir A, Boulware D, Kaiser HE, Lancaster JM, Coppola D, Smith PV, et al.. Cyclooxygenase-2 (COX-2) expression in human endometrial carcinoma and precursor lesions and its possible use in cancer chemoprevention and therapy. In Vivo 2007; 21(1): 35−43.

Ferrandina G, Legge F, Ranelletti FO, Zannoni GF, Maggiano N, Evangelisti A, et al. Cyclooxygenase-2 expression in endometrial carcinoma: correlation with clinicopathologic parameters and clinical outcome. Cancer 2002; 95(4): 801−7.

Nofech-Mozes S, Kupets R, Rasty G, Ismiil N, Covens A, Khalifa MA. Cyclooxygenase 2 (COX-2) Immunostaining Does Not Correlate With the Degree of Vulvar Neoplasia. J Obstet Gy-naecol Can 2006; 28(4): 290−4.

Young JL, Jazaeri AA, Darus CJ, Modesitt SC. Cyclooxygenase-2 in cervical neoplasia: A review. Gynecol Oncol 2008; 109(1): 140−5.

Subbaramaiah K, Dannenberg AJ. Cyclooxygenase-2 transcription is regulated by human papillomavirus 16 E6 and E7 onco-proteins: evidence of a corepressor/coactivator exchange. Cancer Res 2007; 67(8): 3976−85.

Farley J, Uyehara C, Hashiro G, Belnap C, Birrer M, Salminen E. Cyclooxygenase-2 expression predicts recurrence of cervical dysplasia following loop electrosurgical excision procedure. Gynecol Oncol 2004; 92(2): 596−602.

Kim JY, Lim SJ, Park K, Lee C, Kim J. Cyclooxygenase-2 and c-erbB-2 expression in uterine cervical neoplasm assessed using tissue microarrays. Gynecol Oncol 2005; 97(2): 337−41.

Dursun P, Yuce K, Usubutun A, Ayhan A. Cyclooxygenase-2 ex-pression in cervical intraepithelial neoplasia III and squamous cell cervical carcinoma, and its correlation with clinicopatho-logic variables. Int J Gynecol Cancer 2007; 17(1): 164−73.

Khunamornpong S, Settakorn J, Sukpan K, Srisomboon J, Ruangvejvo-rachai P, Thorner PS, et al. Cyclooxygenase-2 expression in squamous cell carcinoma of the uterine cervix is associated with lymph node metastasis. Gynecol Oncol 2009; 112(1): 241−7.

Luo C, Zhu R, Wang H, Lu Y. Expression of COX-2 and MMP-9 in cervical carcinoma and their clinical significance. Zhonghua Zhong Liu Za Zhi 2007; 29(7): 526−30. (Chinese)

Manchana T, Triratanachat S, Sirisabya N, Vasuratna A, Termrun-gruanglert W, Tresukosol D. Prevalence and prognostic signific-ance of COX-2 expression in stage IB cervical cancer. Gyne-col Oncol 2006; 100(3): 556−60.

Huang M, Chen Q, Xiao J, Liu C, Zhao X. Prognostic significance of cyclooxygenase-2 in cervical cancer: A meta-analysis. Int J Cancer 2013; 132(2): 363−73.

Kim J, Li S, Kim J, Yeo S, Kim K, Cho M. Cyclooxygenase-2 ex-pression as a predictor of para-aortic lymph node recurrence in uterine cervical cancer. Int J Radiat Oncol Biol Phys 2008; 70(5): 1516−21.

Klimek M, Urbański K, Kojs Z, Karolewski K, Pudełek J, Blecharz P. Role of cyclooxygenase-2 in cervical cancer. Arch Med Sci 2009; 5(3): 303−7.

Staveley-O'Carroll K, Sotomayor E, Montgomery J. Induction of an-tigen-specific T cell anergy: An early event in the course of tumor progression. Proc Natl Acad Sci USA 1998; 95(3): 1178−83.