Skip to main content

Advertisement

SpringerLink
Log in

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

  • Research Article
  • Published:
Tumor Biology

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;367(118):1591–602.

    Article  Google Scholar 

  2. Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer. 2004;4:695–706.

    Article  CAS  PubMed  Google Scholar 

  3. Boutros C, Gary M, Baldwin K, Somasundar P. Gallbladder cancer: past, present and an uncertain future. Surg Oncol. 2012;21:e183–91.

    Article  CAS  PubMed  Google Scholar 

  4. Dutta U. Gallbladder cancer: can newer insights improve the outcome? J Gastroenterol Hepatol. 2012;27:642–53.

    Article  PubMed  Google Scholar 

  5. Coburn NG, Cleary SP, Tan JC, Law CH. Surgery for gallbladder cancer: a population-based analysis. J Am Coll Surg. 2008;207:371–82.

    Article  PubMed  Google Scholar 

  6. Gourgiotis S, Kocher HM, Solaini L, Yarollahi A, Tsiambas E, Salemis NS. Gallbladder cancer. Am J Surg. 2008;196:252–64.

    Article  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. Wagner SD, Ahearne M, Ko FP. The role of BCL6 in lymphomas and routes to therapy. Br J Haematol. 2011;152:3–12.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Google Scholar 

  17. 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.

    CAS  PubMed  Google Scholar 

  18. 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.

    CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100, Tzyou 1st Rd, Kaohsiung 807, Taiwan

    Peir-In Liang

  2. Department of Pathology, Chi-Mei Foundation Medical Center, 901, Zhonghua Rd., Yongkang Dist, Tainan City 710, Taiwan

    Chien-Feng Li & Tzu-Ju Chen

  3. National Institute of Cancer Research, National Health Research Institutes, 367 Shengli Rd, Tainan City 704, Taiwan

    Chien-Feng Li & Li-Tzong Chen

  4. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, 100, Tzyou 1st Rd, Kaohsiung 807, Taiwan

    Chien-Feng Li

  5. Department of Biotechnology, Southern Taiwan University of Science and Technology, 1, Nan-Tai Street, Yongkang Dist, Tainan City 710, Taiwan

    Chien-Feng Li

  6. Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100, Tzyou 1st Rd, Kaohsiung 807, Taiwan

    Li-Tzong Chen

  7. Division of General Surgery, Department of Surgery, Chi-Mei Medical Center, 901, Zhonghua Rd., Yongkang Dist, Tainan City 710, Taiwan

    Ding-Ping Sun

  8. Department of Anesthesiology, Chi-Mei Medical Center, 901, Zhonghua Rd., Yongkang Dist, Tainan City 710, Taiwan

    Chung-Hsi Hsing

  9. College of Medicine, Taipei Medical University, 250, Wu-Hsing Street, Taipei City 110, Taiwan

    Chung-Hsi Hsing

  10. College of Medicine, China Medical University, 91, Hsueh-Shih Road, Taichung City 404, Taiwan

    Han-Ping Hsu

  11. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi-Mei Foundation Medical Center, 901, Zhonghua Rd., Yongkang Dist, Tainan City 710, Taiwan

    Ching-Yih Lin

  12. Department of Leisure, Recreation, and Tourism Management, Southern Taiwan University of Science and Technology, 1, Nan-Tai Street, Yongkang Dist, Tainan City 710, Taiwan

    Ching-Yih Lin

Authors
  1. Peir-In Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chien-Feng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li-Tzong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ding-Ping Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tzu-Ju Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chung-Hsi Hsing
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Han-Ping Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ching-Yih Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ching-Yih Lin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-013-1195-z

Keywords

Search

Navigation