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01-05-2007 | Original Article

Expression of nuclear factor κB in human gastric carcinoma: relationship with IκBa and prognostic significance

Authors: Georgia Levidou, Penelope Korkolopoulou, Nikolaos Nikiteas, Nikolaos Tzanakis, Irene Thymara, Angelica A. Saetta, Christos Tsigris, George Rallis, Konstantin Vlasis, Efstratios Patsouris

Published in: Virchows Archiv | Issue 5/2007

Abstract

Nuclear factor (NF)-κB is a transcription factor constitutively activated in various neoplasms, including gastric carcinoma. However, its clinical significance in the latter remains an unresolved issue, as published information is limited and controversial. Furthermore, no data is available about the interaction of NFκB with its inhibitory protein IκBa in gastric carcinoma cases. In this study, the expression of NFκB1/p50 and pIκBa protein was evaluated immunohistochemically in paraffin-embedded tissues from 93 patients. The effect of NFκB1/p50 and pIκBa on clinical outcome was assessed. Positive immunostaining was detected for nuclear NFκB1/p50, cytoplasmic NFκB1/p50 and pIκBa in 91, 68 and 85.7% of cases, respectively. A positive correlation emerged between nuclear NFκB1/p50 and pIκBa (p < 0.0001) and a negative one between cytoplasmic NFκB1/p50 and pIκBa (p = 0.0033). Nuclear NFκB1/p50 was associated with stage (p = 0.0388), the depth of invasion (p = 0.0382), World Health Organization (WHO; p = 0.0326) and Lauren’s histological classification (p = 0.0046). NFκB1/p50 nuclear expression adversely affected survival in both univariate and multivariate analysis (p < 0.0001 and p = 0.02, respectively). Our results suggest that NFκB1/p50 nuclear expression and therefore activation is regulated by its interaction with IκBa and that the former may serve as a useful independent molecular marker for stratifying patients with gastric carcinoma in terms of prognosis.

Abdel-Latif MM, 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 239:491–499PubMedCrossRef

Baldwin AS (1996) The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 14:649–683PubMedCrossRef

Bargou RC, Leng C, Krappmann D, Emmerich F, Mapara MY, Bommert K, Royer HD, Scheidereit C, Dorken B (1996) High-level nuclear NF-κB and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells. Blood 87:4340–4347PubMed

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 47:145–149PubMedCrossRef

Chen FE, Ghosh G (1999) Regulation of DNA binding by Rel/NFκB transcription factors: structural reviews. Oncogene 18:6845–6852PubMedCrossRef

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 18:2567–2577PubMedCrossRef

Dolcet X, Llobet D, Pallares J, Matias-Guiu X (2005) NF-kappaB in development and progression of human cancer. Virchows Arch 5:475–482CrossRef

Feinman R, Koury J, Thames M, Barlogie B, Epstein J, Siegel DS (1999) Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood 93:3044–3052PubMed

Ghiorzo P, Mantelli M, Gargiulo S, Gramigni C, Pastorino L, Banelli B, Villaggio B, Coccia MC, Sementa AR, Garre C, Bianchi-Scarra G (2004) Inverse correlation between p16INK4A expression and NF-κB activation in melanoma progression. Hum Path 35:1029–1037PubMedCrossRef

10.

Ghosh S, May M, Kopp EB (1998) NFκB and Rel proteins: evolutionary conserved mediators of immune responses. Annu Rev Immunol 16:225–260PubMedCrossRef

11.

Gilmore TD (1999) The Rel/NFκB signal transduction pathway: introduction. Oncogene 18:6842–6844PubMedCrossRef

12.

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 273:14008–14014PubMedCrossRef

13.

Hamilton SR, Aaltonen LA (2000) World Health Organization classification of tumours-pathology and genetics of the digestive system, pp 38, 43–46

14.

Horiguchi Y, Kuroda K, Nakashima J, Murai M, Umezawa K (2003) Antitumour effect of a novel nuclear factor-kappa B activation inhibitor in bladder cancer cells. Expert Rev Anticancer Ther 6:793–798CrossRef

15.

Ito CY, Adey N, Bautch VL, Baldwin AS Jr (1995) Structure and elocution of the human IκBA gene. Genomics 29:490–495PubMedCrossRef

16.

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 5:748–754CrossRef

17.

Jackel MC (1998) Genetic control of programmed cell death (apoptosis). Prospects for biological tumour staging? HNO 46:614–625PubMedCrossRef

18.

Karin M (1999) How NFκB is activated: the role of IκB kinase (IKK) complex. Oncogene 18:6867–6874PubMedCrossRef

19.

Karin M, Cao Y, Greten FR, Li AW (2002) NFκB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2:301–310PubMedCrossRef

20.

Lee BL, Lee HS, Jung J, Cho SJ, Chung HY, Kim WH, Jin YW, Kim CS, Nam SY (2005) Nuclear factor-kappaB activation correlates with better prognosis and Akt activation in human gastric cancer. Clin Cancer Res 7:2518–2525CrossRef

21.

Macri A, Versaci A, Loddo S, Scuderi G, Travagliante M, Trimarchi G, Teti D, Famulari C (2006) Serum levels of interleukin 1beta, interleukin 8 and tumour necrosis factor alpha as markers of gastric cancer. Biomarkers 2:184–193CrossRef

22.

Mrena J, Wiksten JP, Nordling S, Kokkola A, Ristimaki A, Haglund C (2006) MMP-2 but not MMP-9 associated with COX-2 and survival in gastric cancer. J Clin Pathol 59(6):618–623PubMedCrossRef

23.

Mukhopadhyay T, Roth JA, Maxwell SA (1995) Altered expression of the p50 subunit of the NF-kappaB transcription factor complex in non-small cell lung carcinoma. Oncogene 11:999–1003PubMed

24.

Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ, Sledge GW (1997) Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 17:3629–3639PubMed

25.

Orlowski JR, Baldwin AS (2002) NFκB as a therapeutic target in cancer. Trends Mol Med 8:385–389CrossRef

26.

Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 2:533–543PubMedCrossRef

27.

Rayet B, Gelinas C (1999) Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18:6938–6947PubMedCrossRef

28.

Ross JS, Kallakury BV, Sheehan CE, Fisher HA, Kaufman RP Jr, Kaur P, Gray K, Stringer B (2004) Expression of nuclear factor-κB and IκB proteins in prostatic adenocarcinomas: correlation of nuclear factor-κB immunoreactivity with disease recurrence. Clin Cancer Res 10:2466–2472PubMedCrossRef

29.

Sasaki N, Morisaki T, Hashizume K, Yao T, Tsuneyoshi M, Noshiro H, Nakamura K, Yamanaka T, Uchinaya A, Tabaka M, Katano M (2001) Nuclear factor-κB (RelA) trascription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res 7:4136–4142PubMed

30.

Shattuck-Brandt RL, Richmond A (1997) Enhanced degradation of IκB contributes to endogenous activation of NF-B in Hs294T melanoma cells. Cancer Res 57:3032–3039PubMed

31.

Shibata W, Hirata Y, Yoshida H, Otsuka M, Hoshida Y, Ogura K, Maeda S, Ohmae T, Yanai A, Mitsuno Y, Seki N, Kawabe T, Omata M (2005) NF-kappaB and ERK-signaling pathways contribute to the gene expression induced by cag PAI-positive-Helicobacter pylori infection. World J Gastroenterol 39:6134–6143

32.

Smith MG, Hold GL, Tahara E, El-Omar EM (2006) Cellular and molecular aspects of gastric cancer. World J Gastroenterol 12(19):2979–2990PubMed

33.

Tai DI, Tsai SL, Chang YH, Huang SN, Chen TC, Chang KS, Liaw YF (2000) Constitutive activation of nuclear factor kappaB in hepatocellular carcinoma. Cancer 89(11):2274–2281PubMedCrossRef

34.

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 15:1987–1994PubMedCrossRef

35.

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 5:119–127PubMed

36.

Wang W, Luo HS, Yu BP (2004) Expression of NFκB and human telomerase reverse transcriptase in gastric cancer and precancerous lesions. World J Gastroenterol 2:177–181

37.

Wu CY, Wang CJ, Tseng CC, Chen HP, Wu MS, Lin JT, Inoue H, Chen GH (2005) Helicobacter pylori promote gastric cancer cells invasion through a NF-kappaB and COX-2-mediated pathway. World J Gastroenterol 21:3197–3203

38.

Yamanaka N, Sasaki N, Tasaki A, Nakashima H, Kubo M, Morisaki T, Noshiro H, Yao T, Tsuneyoshi M, Tanaka M, Katano M (2004) Nuclear factor-kappaB p65 is a prognostic indicator in gastric carcinoma. Anticancer Res 24:1071–1075PubMed

39.

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 20:7334–7343CrossRef

40.

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 7:924–932CrossRef

41.

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 1:243–248CrossRef

42.

Zhao XH, Gu SZ, Tian HG, Quan P, Pan BR (2005) Clinical significance of expression of apoptotic signal proteins in gastric carcinoma tissue. World J Gastroenterol 25:3846–3849

Title: Expression of nuclear factor κB in human gastric carcinoma: relationship with IκBa and prognostic significance
Authors: Georgia Levidou
Penelope Korkolopoulou
Nikolaos Nikiteas
Nikolaos Tzanakis
Irene Thymara
Angelica A. Saetta
Christos Tsigris
George Rallis
Konstantin Vlasis
Efstratios Patsouris
Publication date: 01-05-2007
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 5/2007
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-007-0396-5

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Expression of nuclear factor κB in human gastric carcinoma: relationship with IκBa and prognostic significance

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