Abstract
Nuclear factor (NF)-κB has been reported to be constitutively activated in various human neoplasms. However, its clinical significance in bladder urothelial carcinoma (UC) remains an unresolved issue. We conducted this study trying to elucidate the role of NFκB in bladder UC and its potential prognostic significance, by quantifying immunohistochemically the levels of p65/RelA expression in paraffin-embedded tissue from 116 patients. Some of the cases had previously been stained for cellular FLICE-like inhibitory protein (c-FLIP) and bcl-2. Seventy-four cases displayed concurrent cytoplasmic and nuclear immunoreactivity, whereas 18 only nuclear immunoexpression and 21 only cytoplasmic immunoexpression, and the remaining three cases were negative for p65/RelA. Nuclear p65/RelA expression was positively associated with tumour grade and T-category (p = 0.0001 in both cases). In addition, cytoplasmic p65/RelA expression was lower in advanced T-category (p = 0.0030). Moreover, p65/RelA nuclear expression was positively correlated with c-FLIP (p = 0.0109) and bcl-2 (p = 0.0452). p65/RelA nuclear expression adversely affected survival in both univariate and multivariate analysis in superficial (Ta–T1; p = 0.0010 and p = 0.0008) as well as in muscle-invasive carcinomas (T2–T4; p = 0.0004 and p = 0.0003). Our results demonstrate that NF-κB nuclear expression is correlated with histologic grade and T category in bladder UC. Moreover, NF-κB nuclear expression emerges as an independent prognosticator of adverse significance, conveying information beyond that obtained by standard clinicopathological prognosticators.
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Abdel-Latif MMM, O’Riodan J, Windle HJ, Carton E, Ravi N, Kelleher D, Reynolds JV (2004) NF-κB activation in esophageal adenocarcinoma. relationship to Barrett’s metaplasia, survival, and response to neoadjuvant chemoradiotherapy. Ann Surg 239:491–499
Abdel-Mageed AB, Ghoniem GM (1998) Potential role of Rel/Nuclear factor-jB in the pathogenesis of interstitial cystitis. J Urol 160:2000
Baldwin AS (1996) The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 14:649–683
Bours V, Dejardin E, Goujon-Letawe F, Merville MP, Castronovo V (1994) The NF-κB transcription factor and cancer: high expression of NF-κB and IκB-related proteins in tumour cell lines. Biochem Pharmacol 47:145–149
Chen FE, Ghosh G (1999) Regulation of DNA binding by Rel/NFκB transcription factors: structural reviews. Oncogene 18:6845–6852
Dejardin E, Deregowski V, Chapelier M, Jacobs N, Gielen J, Merville MP, Bours V (1999) Regulation of NF kappa B activity by I kappaB-related proteins in adenocarcinoma cells. Oncogene 18:2567–2577
Dhawan P, Singh AB, Ellis DL, Richmond A (2002) Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Res 62:7335–7342
Dolcet X, Llobet D, Pallares J, Matias-Guiu X (2005) NF-κB in development and progression of human cancer. Virchows Arch 5:475–482
Eble JN, Young RH (1997) Carcinoma of the urinary bladder: a review of its diverse morphology. Semin Diagn Pathol 14:98–108
Eble JN, Epstein JI, Seternhenn IA (2004) World Health Organization classification of tumours. Pathology and genetics, tumours of the urinary system and male genital track. IARC, Lyon, pp 89–115
Feinman R, Koury J, Thames M, Barlogie B, Epstein J, Siegel DS (1999) Role of NF- B in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood 93:3044–3052
Gasparian AV, Yao YJ, Kowalczyk D, Lyakh LA, Karseladze A, Slaga TJ, Budunova IV (2002) The role of IKK in constitutive activation of NF-kappaB transcription factor in prostate carcinoma cells. J Cell Sci 115:141–151
Ghosh S, May M, Kopp EB (1998) NFκB and Rel proteins: evolutionary conserved mediators of immune responses. Annu Rev Immunol 16:225–260
Gilmore TD (2006) Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 25(51):6680–6684
Giri DK, Aggarwal BB (1998) Constitutive activation of NF- B causes resistance to apoptosis in human cutaneous T cell lymphoma HuT-78 cells. Autocrine role of tumour necrosis factor and reactive oxygen intermediates. J Biol Chem 273:14008–14014
Greenlee RT, Murray T, Bolden S, Wingo PA (2000) Cancer statistics 2000. CA Cancer J Clin 50:7–33
Hayashi S, Yamamoto M, Ueno Y, Ikeda K, Ohshima K, Soma G et al (2001) Expression of nuclear factor-kappa B, tumor necrosis factor receptor type 1, and c-Myc in human astrocytomas. Neurol Med Chir (Tokyo) 41(4):187–195
Horiguchi Y, Kuroda K, Nakashima J, Murai M, Umezawa K (2003) Antitumor effect of a novel nuclear factor-kappa B activation inhibitor in bladder cancer cells. Expert Rev Anticancer Ther 6:793–798
Izzo JG, Malhotra U, Wu TT, Ensor J, Luthra R, Lee JH, Swisher SG, Liao Z, Chao KS, Hittelman WN, Aggarwal BB, Ajani JA (2006) Association of activated transcription factor nuclear factor kappab with chemoradiation resistance and poor outcome in esophageal carcinoma. J Clin Oncol 5:748–754
Jacobson SH, Hylander B, Wretlind B, Brauner A (1994) Interleukin-6 and interleukin-8 in serum and urine in patients with acute pyelonephritis in relation to bacterial-virulence-associated traits and renal function. Nephron 67(2):172–179
Kang S, Kim YB, Kim MH, Yoon KS, Kim JW, Park NH, Song YS, Kang D, Yoo KY, Kang SB, Lee HP (2005) Polymorphism in the nuclear factor kappa-B binding promoter region of cyclooxygenase-2 is associated with an increased risk of bladder cancer. J Can Let 217(1):11–16
Karashima T, Sweeney P, Kamat A, Huang S, Kim SJ, Bar-Eli M, McConkey DJ, Dinney CPN (2003) Nuclear factor-κB mediates angiogenesis and metastasis of human bladder cancer through the regulation of interleukin-8. Clin Cancer Res 9:2786–2797
Karin M (1999) How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex. Oncogene 18(49):6867–6874
Karin M, Cao Y, Greten FR, Li AW (2002) NFκB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2:301–310
Korkolopoulou P, Konstantinidou AE, Christodoulou P, Patsouris E, Thomas-Tsangli E, Kapralos P, Davaris P (2000) Apoptosis in bladder carcinomas detected with monoclonal antibody to single-stranded DNA: relation to cell cycle regulators and survival. Urology 56(3):516–520
Korkolopoulou P, Christodoulou P, Lazaris A, Thomas-Tsagli E, Kapralos P, Papanikolaou A, Kalliteraki I, Davaris P (2001) Prognostic implications of aberrations in p16/pRb pathway in urothelial bladder carcinomas: a multivariate analysis including p53 expression and proliferation markers. Eur Urol 39(2):167–177
Korkolopoulou P, Lazaris AC, Konstantinidou AE, Kavantzas N, Patsouris E, Christodoulou P, Thomas-Tsagli E, Davaris P (2002) Differential expression of bcl-2 family proteins in bladder carcinomas. Relationship with apoptotic rate and survival. Eur Urol 41(3):274–283
Korkolopoulou P, Goudopoulou A, Voutsinas G, Thomas-Tsagli E, Kapralos P, Patsouris E, Saetta AA (2004) C-Flip expression in bladder urothelial carcinomas: its role in resistance to Fas-mediated apoptosis and clinicopathologic correltations. J Urol 63(6):1198–1204
Kruger S, Thorns C, Bohle A, Feller AC (2003) Prognostic significance of a grading system considering tumour heterogenetity in muscle invasive urothelial carcinoma of the urinary bladder. Int Urol Nephrol 35(2):169–173
La Vecchia C, Negri E, D’Avanzo B, Savoldelli R, Franceschi S (1991) Genital and urinary tract diseases and bladder cancer. Cancer Res 51:629–631
Lessard L, Mes-Masson AM, Lamarre L, Wall L, Lattouf JB, Saad F (2003) NF-κB nuclear localization and its prognostic significance in prostate cancer. BJU Int 91:417–420
Levidou G, Korkolopoulou P, Nikiteas N, Tzanakis N, Thymara I, Saetta AA et al (2007) Expression of nuclear factor kappaB in human gastric carcinoma: relationship with IkappaBa and prognostic significance. Virchows Arch 450(5):519–527
Lind DS, Hochwald SN, Malaty J, Rekkas S, Hebig P, Mishra G, Moldawer LL, Copeland EM 3rd, Mackay S (2001) Nuclear factor-kappa B is upregulated in colorectal cancer. Surgery 2:363–369
Mikulowski P, Hellsten S (2005) T1G1 urinary bladder carcinoma: Fact or fiction? Scand J Urol Nephrol 39:135–137
Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ, Sledge GW (1997) Constitutive activation of NF- B during progression of breast cancer to hormone-independent growth. Mol Cell Biol 17:3629–3639
Osman I, Scher H, Zhang ZF, Soos TJ, Hamza R, Eissa S, Khaled H, Koff A, Cordon-Cardo C (1997) Expression of cyclin D1 but not cyclins E and A, is related to progression in bilharzial bladder cancer. Clin Cancer Res 3:2247–2251
Oya M, Takayanagi A, Horiguchi A, Mizuno R, Ohtsubo M, Marumo K, Shimizu N, Murai M (2003) Increased nuclear factor-kappa B activation is related to the tumor development of renal cell carcinoma. Carcinogenesis 24(3):377–384
Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18(49):6853–6866
Palayoor ST, Youmell MY, Calderwood SK, Coleman CN, Price BD (1999) Constitutive activation of IκB kinase α and NF-κB in prostate cancer cells is inhibited by ibuprofen. Oncogene 18:7389–7394
Perkins ND (2000) The Rel/NF-kappa B family: friend and foe. Trends Biochem Sci 9:434–440
Pryor JP (1973) Factors influencing the survival of patients with transitional cell tumours of the urinary bladder. Br J Urol 45:586–591
Rayet B, Gelinas C (1999) Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18(49):6938–6947
Sasaki N, Morisaki T, Hashizume K, Yao T, Tsuneyoshi M, Noshiro H, Nakamura K, Yamanaka T, Uchiyama A, Tanaka M, Katano M (2001) Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res 12:4136–4142
Schulz WA (2006) Understanding urothelial carcinoma through cancer pathways. Int J Cancer 119(7):1513–1518
Shukla S, MacLennan GT, Fu P, Patel J, Marengo SR, Resnick MI, Gupta S (2004) Nuclear factor-kappaB/p65 (Rel A) is constitutively activated in human prostate adenocarcinoma and correlates with disease progression. Neoplasia 6(4):390–400
Sobin LH, Wittekind C (1997) TNM classification of malignant tumors. Wiley, New York
Suh J, Payvandi F, Edelstein LC, Amenta PS, Zong WX, Gelinas C, Rabson AB (2002) Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells. Prostate 52(3):183–200
Thanos D, Maniatis T (1995) NF-κB: a lesson in family values. Cell 80:529–532
Tojima Y, Fujimoto A, Delhase M, Chen Y, Hatakeyama S, Nakayama K, Kaneko Y, Nimura Y, Motoyama N, Ikeda K, Karin M, Nakanishi M (2000) NAK is an IkappaB kinase-activating kinase. Nature 404(6779):778–782
Visconti R, Cerutti J, Battista S, Fedele M, Trapasso F, Zeki K, Miano MP, Nigris F, Casalino L, Curcio F, Santoro M, Fusco A (1997) Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NF-κB p65 protein expression. Oncogene 15:1987–1994
Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ (1999) The nuclear factor-κB/RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 5:119–127
Wang XC, Saban R, Kaysen JS, Saban MR, Allen PL, Benes EN, Hammond TG (2000) Nuclear factor kappa B mediates lipopolysaccharide-induced inflammation in the urinary bladder. J Urol 163(3):993–998
Williams GT (1991) Programmed cell death: apoptosis and oncogenesis. Cell 65(7):1097–1098
Xie DH, Tang XD, Xia SJ, Tan JM, Wang XH, Cai Y (2002) Expression of NF-kappa B in human bladder cancer and its clinical significance. Ai Zheng 21(6):663–667
Zhang J, Peng B, Chen X (2005) Expressions of nuclear factor kappaB, inducible nitric oxide synthase, and vascular endothelial growth factor in adenoid cystic carcinoma of salivary glands: correlations with the angiogenesis and clinical outcome. Clin Cancer Res 20:7334–7343
Zhang PL, Pellitteri PK, Law A, Gilroy PA, Wood GC, Kennedy TL, Blasick TM, Lun M, Schuerch C 3rd, Brown RE (2005) Overexpression of phosphorylated nuclear factor- kappa B in tonsillar squamous cell carcinoma and high-grade dysplasia is associated with poor prognosis. Mod Pathol 7:924–932
Zhang Z, Ma J, Li N, Sun N, Wang C (2006) Expression of nuclear factor-kappaB and its clinical significance in non small-cell lung cancer. Ann Thorac Surg 1:243–248
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Georgia Levidou, Angelica A. Saetta, Penelope Korkolopoulou have equally contributed to the manuscript.
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Levidou, G., Saetta, A.A., Korkolopoulou, P. et al. Clinical significance of nuclear factor (NF)-κB levels in urothelial carcinoma of the urinary bladder. Virchows Arch 452, 295–304 (2008). https://doi.org/10.1007/s00428-007-0560-y
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DOI: https://doi.org/10.1007/s00428-007-0560-y