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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2016

Open Access 01-12-2016 | Research

Clinical significance of T-bet, GATA-3, and Bcl-6 transcription factor expression in bladder carcinoma

Authors: Islem Ben Bahria-Sediki, Nadhir Yousfi, Catherine Paul, Mohamed Chebil, Mohamed Cherif, Rachida Zermani, Amel Ben Ammar El Gaaied, Ali Bettaieb

Published in: Journal of Translational Medicine | Issue 1/2016

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Abstract

Background

The aim of this study was to investigate the clinical significance of three immune cell-related transcription factors, T-bet, GATA-3 and Bcl-6 in bladder cancer in Tunisian patients.

Methods

Expression of T-bet, GATA-3 and Bcl-6 genes was assessed using RT-qPCR in 65 bladder cancers from patients: 32 being diagnosed as low- and medium-grade, 31 as high-grade, 25 as muscle invasive stage and 39 as non-muscle invasive stage. Gene expression was statistically correlated according to the grade, the stage, tobacco consumption, the BCG response and disease severity.

Results

T-bet levels in patients with high-grade bladder cancer were significantly elevated compared to patients with low- or medium-grade bladder cancer (p = 0.005). In invasive carcinoma (T2–T4), the T-bet levels were significantly higher than in superficial non-invasive bladder tumors (Tis, Ta, and T1) (p = 0.02). However, T-bet is predictive of the response to BCG. Its expression is high in good responders to BCG (p = 0.02). In contrast, the expression of GATA-3 and Bcl-6 in non-invasive carcinoma (p = 0.008 and p = 0.0003) and in patients with low- and medium-grade cancers (p = 0.001 and p < 0.0001) is significantly higher than in invasive bladder tumors and in patients with high-grade bladder carcinoma, respectively. In addition, heavy smokers, whose tumors express low levels of GATA-3 and Bcl-6, are poor responders to BCG (p = 0.01 and p = 0.03). Finally, better patient survival correlated with GATA-3 (p = 0.04) and Bcl-6 (p = 0.04) but not T-bet expression.

Conclusions

Our results suggest that T-bet expression in bladder tumors could be a positive prognostic indicator of BCG therapy, even if high levels are found in high-grade and stage of the disease. However, GATA-3 and Bcl-6 expression could be considered as predictive factors for good patient survival.
Literature
1.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.CrossRefPubMed
2.
Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353(25):2654–66.CrossRefPubMed
3.
Atreya I, Schimanski CC, Becker C, Wirtz S, Dornhoff H, Schnurer E, et al. The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer. Gut. 2007;56(11):1572–8.CrossRefPubMedPubMedCentral
4.
Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science. 2001;292(5523):1907–10.CrossRefPubMed
5.
Lazarevic V, Glimcher LH, Lord GM. T-bet: a bridge between innate and adaptive immunity. Nat Rev Immunol. 2013;13(11):777–89.CrossRefPubMed
6.
Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA. 2007;104(10):3967–72.CrossRefPubMedPubMedCentral
7.
Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102(51):18538–43.CrossRefPubMedPubMedCentral
8.
Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27(2):186–92.CrossRefPubMed
9.
10.
Ziegler A, Heidenreich R, Braumuller H, Wolburg H, Weidemann S, Mocikat R, et al. EpCAM, a human tumor-associated antigen promotes Th2 development and tumor immune evasion. Blood. 2009;113(15):3494–502.CrossRefPubMed
11.
Evans CF, Galustian C, Bodman-Smith M, Dalgleish AG, Kumar D. The effect of colorectal cancer upon host peripheral immune cell function. Colorectal Dis. 2010;12(6):561–9.CrossRefPubMed
12.
Kemp RA, Ronchese F. Tumor-specific Tc1, but not Tc2, cells deliver protective antitumor immunity. J Immunol. 2001;167(11):6497–502.CrossRefPubMed
13.
Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011;71(4):1263–71.CrossRefPubMed
14.
Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, et al. The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun. 2008;374(3):533–7.CrossRefPubMed
15.
16.
Wu Q, Liu X, Yan H, He YH, Ye S, Cheng XW, et al. B-cell lymphoma 6 protein stimulates oncogenicity of human breast cancer cells. BMC Cancer. 2014;14:418.CrossRefPubMedPubMedCentral
17.
Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, et al. CD4(+) follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013;123(7):2873–92.CrossRefPubMedPubMedCentral
18.
Jia Y, Zeng Z, Li Y, Li Z, Jin L, Zhang Z, et al. Impaired function of CD4+ T follicular helper (Tfh) cells associated with hepatocellular carcinoma progression. PLoS One. 2015;10(2):e0117458.CrossRefPubMedPubMedCentral
19.
Krpina K, Babarović EN. Correlation of tumor-infiltrating lymphocytes with bladder cancer recurrence in patients with solitary low-grade urothelial carcinoma. Virchows Arch. 2015;467(4):443–8.CrossRefPubMed
20.
Parodi A, Traverso P, Kalli F, Conteduca G, Tardito S, Curto M, Grillo F, Mastracci L, Bernardi C, Nasi G, Minaglia F, Simonato A, Carmignani G, Ferrera F, Fenoglio D, Filaci G. Residual tumor micro-foci and overwhelming regulatory T lymphocyte infiltration are the causes of bladder cancer recurrence. Oncotarget. 2016;7(6):6424–35.PubMed
21.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed
22.
Babjuk M, Burger M, Zigeuner R, Shariat SF, van Rhijn BW, Comperat E, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol. 2013;64(4):639–53.CrossRefPubMed
23.
Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100(6):655–69.CrossRefPubMed
24.
Brandacher G, Winkler C, Schroecksnadel K, Margreiter R, Fuchs D. Antitumoral activity of interferon-gamma involved in impaired immune function in cancer patients. Curr Drug Metab. 2006;7(6):599–612.CrossRefPubMed
25.
Oh S, Hwang ES. The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. J Immunol Res. 2014;2014:589672.CrossRefPubMedPubMedCentral
26.
Prescott S, James K, Hargreave TB, Chisholm GD, Smyth JF. Intravesical Evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall. J Urol. 1992;147(6):1636–42.PubMed
27.
Ratliff TL, Ritchey JK, Yuan JJ, Andriole GL, Catalona WJ. T-cell subsets required for intravesical BCG immunotherapy for bladder cancer. J Urol. 1993;150(3):1018–23.PubMed
28.
Zuiverloon TC, Nieuweboer AJ, Vekony H, Kirkels WJ, Bangma CH, Zwarthoff EC. Markers predicting response to bacillus Calmette-Guerin immunotherapy in high-risk bladder cancer patients: a systematic review. Eur Urol. 2012;61(1):128–45.CrossRefPubMed
29.
Higgins JP, Kaygusuz G, Wang L, Montgomery K, Mason V, Zhu SX, et al. Placental S100 (S100P) and GATA3: markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray. Am J Surg Pathol. 2007;31(5):673–80.CrossRefPubMed
30.
Asch-Kendrick R, Cimino-Mathews A. The role of GATA3 in breast carcinomas: a review. Hum Pathol. 2016;48:37–47.CrossRefPubMed
31.
Huang M, Wang J, Lee P, Sharma S, Mao JT, Meissner H, Uyemura K, Modlin R, Wollman J, Dubinett SM. Human non-small cell lung cancer cells express a type 2 cytokine pattern. Cancer Res. 1995;55(17):3847–53.PubMed
32.
Agarwal A, Rani M, Saha GK, Valarmathi TM, Bahadur S, Mohanti BK, Das SN. Disregulated expression of the Th2 cytokine gene in patients with intraoral squamous cell carcinoma. Immunol Invest. 2003;32(1–2):17–30.CrossRefPubMed
33.
Bais AG, Beckmann I, Lindemans J, Ewing PC, Meijer CJ, Snijders PJ, Helmerhorst TJ. A shift to a peripheral Th2-type cytokine pattern during the carcinogenesis of cervical cancer becomes manifest in CIN III lesions. J Clin Pathol. 2005;58(10):1096–100.CrossRefPubMedPubMedCentral
34.
Agarwal A, Verma S, Burra U, Murthy NS, Mohanty NK, Saxena S. Flow cytometric analysis of Th1 and Th2 cytokines in PBMCs as a parameter of immunological dysfunction in patients of superficial transitional cell carcinoma of bladder. Cancer Immunol Immunother. 2006;55(6):734–43.CrossRefPubMed
35.
Nunez-Nateras R, Castle EP, Protheroe CA, Stanton ML, Ocal TI, Ferrigni EN, Ochkur SI, Jacobsen EA, Hou YX, Andrews PE, Colby TV, Lee NA, Lee JJ. Predicting response to bacillus Calmette-Guérin (BCG) in patients with carcinoma in situ of the bladder. Urol Oncol. 2014;32(1):45.e23–30.CrossRef
36.
Duan S, Cermak L, Pagan JK, Rossi M, Martinengo C, di Celle PF, et al. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature. 2012;481(7379):90–3.CrossRefPubMedPubMedCentral
37.
Lin Z, Kim H, Park H, Kim Y, Cheon J, Kim I. The expression of bcl-2 and Bcl-6 protein in normal and malignant transitional epithelium. Urol Res. 2003;31(4):272–5.CrossRefPubMed
38.
Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39(4):782–95.CrossRefPubMed
39.
Simonis K, Shariat SF, Rink M. Urothelial Cancer Working Group of the Young Academic Urologists (YAU) Working Party of the European Association of Urology (EAU). Smoking and smoking cessation effects on oncological outcomes in nonmuscle invasive bladder cancer. Curr Opin Urol. 2014;24(5):492–9.CrossRefPubMed
40.
Metadata
Title
Clinical significance of T-bet, GATA-3, and Bcl-6 transcription factor expression in bladder carcinoma
Authors
Islem Ben Bahria-Sediki
Nadhir Yousfi
Catherine Paul
Mohamed Chebil
Mohamed Cherif
Rachida Zermani
Amel Ben Ammar El Gaaied
Ali Bettaieb
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2016
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-016-0891-z

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