Abstract
B cell lymphoma 6 (BCL6) is a protein that is vital for lymphogenesis. Its expression has been well established in lymphoma, especially in diffuse large B-cell lymphoma. Its role in carcinogenesis is less well understood. Previous study shows that BCL6 expression may regulate p19 functions, an important regulator for the p53 pathway. No prior study has attempted to evaluate the significance of BCL6 and p19ARF expression in a large cohort of patients with gallbladder carcinomas (GBCs). We selected 164 patients with GBC and performed immunostains for BCL6 and p19ARF. BCL6 expression and p19ARF expression were evaluated using a histochemical score (H-score). We then correlated the results with various clinicopathological factors, disease-specific survival (DSS), and disease-free survival (DFS). BCL6 overexpression was significantly associated with high pT status, high TNM stage, higher histological grade (p = 0.029), vascular invasion, perineurial invasion, high Ki-67 labeling index, and low p19 expression. Importantly, BCL6 overexpression in GBC was strongly associated with worse DSS (p < 0.0001) and DFS (p < 0.0001) in the univariate analysis, and remained independently predictive of adverse outcomes (p = 0.001, hazard ratio (H.R.) = 3.098 for DSS; p = 0.002, H.R. = 2.255 for DFS). Low p19ARF expression was correlated with a poor DSS (p = 0.0144) and DFS (p = 0.0032) in the univariate analysis but was not prognosticatory in the multivariate analysis. In GBC, BCL6 overexpression correlated with adverse phenotypes and decreased p19ARF expression. BCL6 overexpression also independently predicts worse DSS and DFS, suggesting it has a role in tumorigenesis or carcinogenesis and could be a potential prognostic indicator in GBC.
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Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;367(118):1591–602.
Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer. 2004;4:695–706.
Boutros C, Gary M, Baldwin K, Somasundar P. Gallbladder cancer: past, present and an uncertain future. Surg Oncol. 2012;21:e183–91.
Dutta U. Gallbladder cancer: can newer insights improve the outcome? J Gastroenterol Hepatol. 2012;27:642–53.
Coburn NG, Cleary SP, Tan JC, Law CH. Surgery for gallbladder cancer: a population-based analysis. J Am Coll Surg. 2008;207:371–82.
Gourgiotis S, Kocher HM, Solaini L, Yarollahi A, Tsiambas E, Salemis NS. Gallbladder cancer. Am J Surg. 2008;196:252–64.
Ozenne P, Eymin B, Brambilla E, Gazzeri S. The ARF tumor suppressor: structure, functions and status in cancer. Int J Cancer. 2010;127:2239–47.
Silva J, Domínguez G, Silva JM, García JM, Gallego I, Corbacho C, et al. Analysis of genetic and epigenetic processes that influence p14ARF expression in breast cancer. Oncogene. 2001;20:4586–90.
Hsu HS, Wang YC, Tseng RC, Chang JW, Chen JT, Shih CM, et al. 5' cytosine-phospho-guanine island methylation is responsible for p14ARF inactivation and inversely correlates with p53 overexpression in resected non-small cell lung cancer. Clin Cancer Res. 2004;10:4734–41.
Lee M, Sup Han W, Kyoung Kim O, Hee Sung S, Sun Cho M, Lee SN, et al. Prognostic value of p16INK4a and p14ARF gene hypermethylation in human colon cancer. Pathol Res Pract. 2006;202:415–24.
Jardin F, Ruminy P, Bastard C, Tilly H. The BCL6 proto-oncogene: a leading role during germinal center development and lymphomagenesis. Pathol Biol (Paris). 2007;55:73–83.
Wagner SD, Ahearne M, Ko FP. The role of BCL6 in lymphomas and routes to therapy. Br J Haematol. 2011;152:3–12.
Shvarts A, Brummelkamp TR, Scheeren F, Koh E, Daley GQ, Spits H, et al. A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling. Genes Dev. 2002;16:681–6.
Pinto AE, André S, Silva G, Vieira S, Santos AC, Dias S, et al. BCL-6 oncoprotein in breast cancer: loss of expression in disease progression. Pathobiology. 2009;76:235–42.
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;31:272–5.
Sun DP, Lin CY, Tian YF, Chen LT, Lin LC, Lee SW, et al. Clinicopathological significance of HuR expression in gallbladder carcinoma: with special emphasis on the implications of its nuclear and cytoplasmic expression. Tumour Biol. 2013. doi:10.1007/s13277-013-0872-2.
Budwit-Novotny DA, McCarty KS, Cox EB, Soper JT, Mutch DG, Creasman WT, et al. Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res. 1986;46:5419–25.
McClelland RA, Finlay P, Walker KJ, Nicholson D, Robertson JF, Blamey RW, et al. Automated quantitation of immunocytochemically localized estrogen receptors in human breast cancer. Cancer Res. 1990;50:3545–50.
Kanazawa N, Moriyama M, Onizuka T, Sugawara K, Mori S. Expression of bcl-6 protein in normal skin and epidermal neoplasms. Pathol Int. 1997;47:600–7.
Cho HY, Park HS, Lin Z, Kim I, Joo KJ, Cheon J. BCL6 gene mutations in transitional cell carcinomas. J Int Med Res. 2007;35:224–30.
Logarajah S, Hunter P, Kraman M, Steele D, Lakhani S, Bobrow L, et al. BCL-6 is expressed in breast cancer and prevents mammary epithelial differentiation. Oncogene. 2003;22:5572–8.
Bos R, van Diest PJ, van der Groep P, Greijer AE, Hermsen MA, Heijnen I, et al. Protein expression of B-cell lymphoma gene 6 (BCL-6) in invasive breast cancer is associated with cyclin D1 and hypoxia-inducible factor-1alpha (HIF-1alpha). Oncogene. 2003;22:8948–51.
Gorunova L, Parada LA, Limon J, Jin Y, Hallén M, Hägerstrand I, et al. Nonrandom chromosomal aberrations and cytogenetic heterogeneity in gallbladder carcinomas. Genes Chromosomes Cancer. 1999;26:312–21.
Cerchietti LC, Ghetu AF, Zhu X, Da Silva GF, Zhong S, Matthews M, et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell. 2010;17:400–11.
Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H, Swaminathan S, et al. BCL6 enables Ph + acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. Nature. 2011;473:384–8.
Sailasree R, Abhilash A, Sathyan KM, Nalinakumari KR, Thomas S, Kannan S. Differential roles of p16INK4A and p14ARF genes in prognosis of oral carcinoma. Cancer Epidemiol Biomarkers Prev. 2008;17:414–20.
Kwong RA, Kalish LH, Nguyen TV, Kench JG, Bova RJ, Cole IE, et al. p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the anterior tongue. Clin Cancer Res. 2005;11:4107–16.
Dominguez G, Silva J, Garcia JM, Silva JM, Rodriguez R, Muñoz C, et al. Prevalence of aberrant methylation of p14ARF over p16INK4a in some human primary tumors. Mutat Res. 2003;530:9–17.
Tsujimoto H, Hagiwara A, Sugihara H, Hattori T, Yamagishi H. Promoter methylations of p16INK4a and p14ARF genes in early and advanced gastric cancer. Correlations of the modes of their occurrence with histologic type. Pathol Res Pract. 2002;198:785–94.
Simon M, Voss D, Park-Simon TW, Mahlberg R, Köster G. Role of p16 and p14ARF in radio- and chemosensitivity of malignant gliomas. Oncol Rep. 2006;16:127–32.
Suzuki H, Kurita M, Mizumoto K, Moriyama M, Aiso S, Nishimoto I, et al. The ARF tumor suppressor inhibits BCL6-mediated transcriptional repression. Biochem Biophys Res Commun. 2005;326:242–8.
Fatyol K, Szalay AA. The p14ARF tumor suppressor protein facilitates nucleolar sequestration of hypoxia-inducible factor-1alpha (HIF-1alpha) and inhibits HIF-1-mediated transcription. J Biol Chem. 2001;276:28421–9.
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This work was supported by grants (NSC101-2320-B-384-001-MY3) from the National Science Council, Taiwan, (100-TMP-009-3 and DOH101-TD-C-111-004) Department of Health, Taiwan, and (100CM-TMU-01) Chi Mei Medical Center, Tainan, Taiwan. The authors also appreciate the BioBank of Chi Mei medical Center to provide the tumor samples.
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Liang, PI., Li, CF., Chen, LT. et al. BCL6 overexpression is associated with decreased p19ARF expression and confers an independent prognosticator in gallbladder carcinoma. Tumor Biol. 35, 1417–1426 (2014). https://doi.org/10.1007/s13277-013-1195-z
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DOI: https://doi.org/10.1007/s13277-013-1195-z