Skip to main content
Erschienen in: Tumor Biology 2/2014

01.02.2014 | Research Article

BCL6 overexpression is associated with decreased p19ARF expression and confers an independent prognosticator in gallbladder carcinoma

verfasst von: Peir-In Liang, Chien-Feng Li, Li-Tzong Chen, Ding-Ping Sun, Tzu-Ju Chen, Chung-Hsi Hsing, Han-Ping Hsu, Ching-Yih Lin

Erschienen in: Tumor Biology | Ausgabe 2/2014

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;367(118):1591–602.CrossRef Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;367(118):1591–602.CrossRef
2.
Zurück zum Zitat Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer. 2004;4:695–706.PubMedCrossRef Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer. 2004;4:695–706.PubMedCrossRef
3.
Zurück zum Zitat Boutros C, Gary M, Baldwin K, Somasundar P. Gallbladder cancer: past, present and an uncertain future. Surg Oncol. 2012;21:e183–91.PubMedCrossRef Boutros C, Gary M, Baldwin K, Somasundar P. Gallbladder cancer: past, present and an uncertain future. Surg Oncol. 2012;21:e183–91.PubMedCrossRef
4.
Zurück zum Zitat Dutta U. Gallbladder cancer: can newer insights improve the outcome? J Gastroenterol Hepatol. 2012;27:642–53.PubMedCrossRef Dutta U. Gallbladder cancer: can newer insights improve the outcome? J Gastroenterol Hepatol. 2012;27:642–53.PubMedCrossRef
5.
Zurück zum Zitat Coburn NG, Cleary SP, Tan JC, Law CH. Surgery for gallbladder cancer: a population-based analysis. J Am Coll Surg. 2008;207:371–82.PubMedCrossRef Coburn NG, Cleary SP, Tan JC, Law CH. Surgery for gallbladder cancer: a population-based analysis. J Am Coll Surg. 2008;207:371–82.PubMedCrossRef
6.
Zurück zum Zitat Gourgiotis S, Kocher HM, Solaini L, Yarollahi A, Tsiambas E, Salemis NS. Gallbladder cancer. Am J Surg. 2008;196:252–64.PubMedCrossRef Gourgiotis S, Kocher HM, Solaini L, Yarollahi A, Tsiambas E, Salemis NS. Gallbladder cancer. Am J Surg. 2008;196:252–64.PubMedCrossRef
7.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
8.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
9.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
10.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
11.
Zurück zum Zitat 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.CrossRef 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.CrossRef
12.
Zurück zum Zitat Wagner SD, Ahearne M, Ko FP. The role of BCL6 in lymphomas and routes to therapy. Br J Haematol. 2011;152:3–12.PubMedCrossRef Wagner SD, Ahearne M, Ko FP. The role of BCL6 in lymphomas and routes to therapy. Br J Haematol. 2011;152:3–12.PubMedCrossRef
13.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
14.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
15.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
16.
Zurück zum Zitat 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. 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.
17.
Zurück zum Zitat 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.PubMed 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.PubMed
18.
Zurück zum Zitat 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.PubMed 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.PubMed
19.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
20.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
21.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
22.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
23.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
24.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
25.
Zurück zum Zitat 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.PubMedCentralPubMedCrossRef 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.PubMedCentralPubMedCrossRef
26.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
27.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
28.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
29.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
30.
Zurück zum Zitat 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.PubMed 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.PubMed
31.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
32.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
Metadaten
Titel
BCL6 overexpression is associated with decreased p19ARF expression and confers an independent prognosticator in gallbladder carcinoma
verfasst von
Peir-In Liang
Chien-Feng Li
Li-Tzong Chen
Ding-Ping Sun
Tzu-Ju Chen
Chung-Hsi Hsing
Han-Ping Hsu
Ching-Yih Lin
Publikationsdatum
01.02.2014
Verlag
Springer Netherlands
Erschienen in
Tumor Biology / Ausgabe 2/2014
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-013-1195-z

Weitere Artikel der Ausgabe 2/2014

Tumor Biology 2/2014 Zur Ausgabe

Adjuvante Immuntherapie verlängert Leben bei RCC

25.04.2024 Nierenkarzinom Nachrichten

Nun gibt es auch Resultate zum Gesamtüberleben: Eine adjuvante Pembrolizumab-Therapie konnte in einer Phase-3-Studie das Leben von Menschen mit Nierenzellkarzinom deutlich verlängern. Die Sterberate war im Vergleich zu Placebo um 38% geringer.

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

25.04.2024 NSCLC Nachrichten

Das Risiko für Rezidiv oder Tod von Patienten und Patientinnen mit reseziertem ALK-positivem NSCLC ist unter einer adjuvanten Therapie mit dem Tyrosinkinase-Inhibitor Alectinib signifikant geringer als unter platinbasierter Chemotherapie.

Bei Senioren mit Prostatakarzinom auf Anämie achten!

24.04.2024 DGIM 2024 Nachrichten

Patienten, die zur Behandlung ihres Prostatakarzinoms eine Androgendeprivationstherapie erhalten, entwickeln nicht selten eine Anämie. Wer ältere Patienten internistisch mitbetreut, sollte auf diese Nebenwirkung achten.

ICI-Therapie in der Schwangerschaft wird gut toleriert

Müssen sich Schwangere einer Krebstherapie unterziehen, rufen Immuncheckpointinhibitoren offenbar nicht mehr unerwünschte Wirkungen hervor als andere Mittel gegen Krebs.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.