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Published in: Diagnostic Pathology 1/2013

Open Access 01-12-2013 | Research

Immunohistochemical analysis of chromatin remodeler DAXX in high grade urothelial carcinoma

Authors: Antonio Zizzi, Maria Alessandra Montironi, Roberta Mazzucchelli, Marina Scarpelli, Antonio Lopez-Beltran, Liang Cheng, Nicola Paone, Paolo Castellini, Rodolfo Montironi

Published in: Diagnostic Pathology | Issue 1/2013

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Abstract

Background/Aims

The chromatin remodeler DAXX, a predominantly nuclear protein, regulates the status of chromatin organization. The aim of this exploratory immunohistochemical study was to evaluate DAXX protein expression in high grade invasive urothelial carcinoma (UC) of the bladder as a biological regulator of aggressiveness.

Methods

Quantitative analysis was made on DAXX immunostained nuclei in tissue sections from 5 cases of bladder normal urothelium (NU) and 5 cases of bladder pT1 UC. Carcinoma in situ (CIS) and high grade papillary carcinoma (HGPCa) were identified in 2 out of 5 UC cases.

Results

The nuclei in UC show an open configuration of the chromatin composed of granules varying in size and distribution and a mean nuclear area 1.7 times greater than that in NU (UC: mean and SD 24.4 ± 11.4 square microns; NU: 14.8 6.5 square microns. The differences are statistically significant). 70% of the NU nuclei are immunostained, whereas 90% of UC nuclei are positive. The mean gray level value in UC, related to the intensity of nuclear immunostaining, is lower than in NU by a factor of 0.94 (UC: mean and SD 100 ± 15; NU: 106 ± 15. The differences are statistically significant). In particular, the value in the nuclei adjacent to the stroma in UC is slightly lower than in the intermediate cell layers by factor of 0.98, whereas in NU it is slightly greater by a factor 1.02 and 1.04 compared to the intermediate and superficial cell layers. The values in CIS and HGPCa are similar to those in UC.

Conclusions

The quantitative immunohistochemical analysis shows an altered protein expression of chromatin remodeler DAXX in UC and in its preinvasive phases, when compared to NU. DAXX evaluation, if associated with markers related to global DNA methylation and histone acetylation, could be used in clinical practice as a marker of aggressiveness.

Virtual slides

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Appendix
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Literature
1.
go back to reference Gårdmark T, Bladström A, Hellsten S, Malmström PU, Members of The Swedish National Bladder Cancer Registry: Analysis of clinical characteristics, management and survival of patients with Ta T1 bladder tumours in Sweden between 1997 and 2001. Scand J Urol Nephrol. 2006, 40: 276-282. 10.1080/00365590600744238.CrossRefPubMed Gårdmark T, Bladström A, Hellsten S, Malmström PU, Members of The Swedish National Bladder Cancer Registry: Analysis of clinical characteristics, management and survival of patients with Ta T1 bladder tumours in Sweden between 1997 and 2001. Scand J Urol Nephrol. 2006, 40: 276-282. 10.1080/00365590600744238.CrossRefPubMed
2.
go back to reference Montironi R, Cheng L, Scarpelli M, Mazzucchelli R, Lopez-Beltran A: How much do you know about benign, preneoplastic, non-invasive and invasive neoplastic lesions of the urinary bladder classified according to the 2004 WHO scheme?. Diagn Pathol. 2011, 6: 31-10.1186/1746-1596-6-31.PubMedCentralCrossRefPubMed Montironi R, Cheng L, Scarpelli M, Mazzucchelli R, Lopez-Beltran A: How much do you know about benign, preneoplastic, non-invasive and invasive neoplastic lesions of the urinary bladder classified according to the 2004 WHO scheme?. Diagn Pathol. 2011, 6: 31-10.1186/1746-1596-6-31.PubMedCentralCrossRefPubMed
3.
go back to reference Segersten MU, Edlund EK, Micke P, De la Torre M, Hamberg H, Edvinsson AE, Andersson SE, Malmström PU, Wester HK: A novel strategy based on histological protein profiling in-silico for identifying potential biomarkers in urinary bladder cancer. BJU Int. 2009, 104: 1780-1785. 10.1111/j.1464-410X.2009.08674.x.CrossRefPubMed Segersten MU, Edlund EK, Micke P, De la Torre M, Hamberg H, Edvinsson AE, Andersson SE, Malmström PU, Wester HK: A novel strategy based on histological protein profiling in-silico for identifying potential biomarkers in urinary bladder cancer. BJU Int. 2009, 104: 1780-1785. 10.1111/j.1464-410X.2009.08674.x.CrossRefPubMed
4.
go back to reference Als AB, Dyrskjøt L, Von der Maase H, Koed K, Mansilla F, Toldbod HE, Jensen JL, Ulhøi BP, Sengeløv L, Jensen KM, Orntoft TF: Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer. Clin Cancer Res. 2007, 13: 4407-4414. 10.1158/1078-0432.CCR-07-0109.CrossRefPubMed Als AB, Dyrskjøt L, Von der Maase H, Koed K, Mansilla F, Toldbod HE, Jensen JL, Ulhøi BP, Sengeløv L, Jensen KM, Orntoft TF: Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer. Clin Cancer Res. 2007, 13: 4407-4414. 10.1158/1078-0432.CCR-07-0109.CrossRefPubMed
5.
go back to reference Birkhahn M, Mitra AP, Cote RJ: Molecular markers for bladder cancer: the road to a multimarker approach. Expert Rev Anticancer Ther. 2007, 7: 1717-1727. 10.1586/14737140.7.12.1717.CrossRefPubMed Birkhahn M, Mitra AP, Cote RJ: Molecular markers for bladder cancer: the road to a multimarker approach. Expert Rev Anticancer Ther. 2007, 7: 1717-1727. 10.1586/14737140.7.12.1717.CrossRefPubMed
6.
go back to reference Knowles MA: Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors. Future Oncol. 2008, 4: 71-83. 10.2217/14796694.4.1.71.CrossRefPubMed Knowles MA: Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors. Future Oncol. 2008, 4: 71-83. 10.2217/14796694.4.1.71.CrossRefPubMed
7.
go back to reference Wang S, Xue S, Dai Y, Yang J, Chen Z, Fang X, Zhou W, Wu W, Li Q: Reduced expression of microRNA-100 confers unfavorable prognosis in patients with bladder cancer. Diagn Pathol. 2012, 7: 159-10.1186/1746-1596-7-159.PubMedCentralCrossRefPubMed Wang S, Xue S, Dai Y, Yang J, Chen Z, Fang X, Zhou W, Wu W, Li Q: Reduced expression of microRNA-100 confers unfavorable prognosis in patients with bladder cancer. Diagn Pathol. 2012, 7: 159-10.1186/1746-1596-7-159.PubMedCentralCrossRefPubMed
8.
go back to reference Barbisan F, Mazzucchelli R, Santinelli A, Stramazzotti D, Scarpelli M, Lopez-Beltran A, Cheng L, Montironi R: Immunohistochemical evaluation of global DNA methylation and histone acetylation in papillary urothelial neoplasm of low malignant potential. Int J Immunopathol Pharmacol. 2008, 21: 615-623.PubMed Barbisan F, Mazzucchelli R, Santinelli A, Stramazzotti D, Scarpelli M, Lopez-Beltran A, Cheng L, Montironi R: Immunohistochemical evaluation of global DNA methylation and histone acetylation in papillary urothelial neoplasm of low malignant potential. Int J Immunopathol Pharmacol. 2008, 21: 615-623.PubMed
9.
go back to reference Mazzucchelli R, Scarpelli M, Lopez-Beltran A, Cheng L, Bartels H, Bartels PH, Alberts DS, Montironi R: Global acetylation and methylation changes predict papillary urothelial neoplasia of low malignant potential recurrence: a quantitative analysis. Int J Immunopathol Pharmacol. 2011, 24: 489-497.PubMedCentralPubMed Mazzucchelli R, Scarpelli M, Lopez-Beltran A, Cheng L, Bartels H, Bartels PH, Alberts DS, Montironi R: Global acetylation and methylation changes predict papillary urothelial neoplasia of low malignant potential recurrence: a quantitative analysis. Int J Immunopathol Pharmacol. 2011, 24: 489-497.PubMedCentralPubMed
11.
go back to reference Drané P, Ouararhni K, Depaux A, Shuaib M, Hamiche A: The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev. 2010, 24: 1253-6125. 10.1101/gad.566910.PubMedCentralCrossRefPubMed Drané P, Ouararhni K, Depaux A, Shuaib M, Hamiche A: The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev. 2010, 24: 1253-6125. 10.1101/gad.566910.PubMedCentralCrossRefPubMed
12.
go back to reference Hollenbach AD, McPherson CJ, Mientjes EJ, Iyengar R, Grosveld G: Daxx and histone deacetylase II associate with chromatin through an interaction with core histones and the chromatin-associated protein Dek. J Cell Sci. 2002, 115: 3319-3330.PubMed Hollenbach AD, McPherson CJ, Mientjes EJ, Iyengar R, Grosveld G: Daxx and histone deacetylase II associate with chromatin through an interaction with core histones and the chromatin-associated protein Dek. J Cell Sci. 2002, 115: 3319-3330.PubMed
13.
go back to reference Tang J, Agrawal T, Cheng Q, Qu L, Brewer MD, Chen J, Yang X: Phosphorylation of Daxx by ATM contributes to DNA damage-induced p53 activation. PLoS One. 2013, 8: e55813-10.1371/journal.pone.0055813.PubMedCentralCrossRefPubMed Tang J, Agrawal T, Cheng Q, Qu L, Brewer MD, Chen J, Yang X: Phosphorylation of Daxx by ATM contributes to DNA damage-induced p53 activation. PLoS One. 2013, 8: e55813-10.1371/journal.pone.0055813.PubMedCentralCrossRefPubMed
14.
go back to reference De Wilde RF, Heaphy CM, Maitra A, Meeker AK, Edil BH, Wolfgang CL, Ellison TA, Schulick RD, Molenaar IQ, Valk GD, Vriens MR, Borel Rinkes IH, Offerhaus GJ, Hruban RH, Matsukuma KE: Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Mod Pathol. 2012, 25: 1033-1039. 10.1038/modpathol.2012.53.PubMedCentralCrossRefPubMed De Wilde RF, Heaphy CM, Maitra A, Meeker AK, Edil BH, Wolfgang CL, Ellison TA, Schulick RD, Molenaar IQ, Valk GD, Vriens MR, Borel Rinkes IH, Offerhaus GJ, Hruban RH, Matsukuma KE: Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Mod Pathol. 2012, 25: 1033-1039. 10.1038/modpathol.2012.53.PubMedCentralCrossRefPubMed
15.
go back to reference Puto LA, Reed JC: Daxx represses RelB target promoters via DNA methyltransferase recruitment and DNA hypermethylation. Genes Dev. 2008, 22: 998-1010. 10.1101/gad.1632208.PubMedCentralCrossRefPubMed Puto LA, Reed JC: Daxx represses RelB target promoters via DNA methyltransferase recruitment and DNA hypermethylation. Genes Dev. 2008, 22: 998-1010. 10.1101/gad.1632208.PubMedCentralCrossRefPubMed
16.
go back to reference Ryo A, Hirai A, Nishi M, Liou YC, Perrem K, Lin SC, Hirano H, Lee SW, Aoki I: A suppressive role of the prolyl isomerase Pin1 in cellular apoptosis mediated by the death-associated protein Daxx. J Biol Chem. 2007, 282: 36671-36681. 10.1074/jbc.M704145200.CrossRefPubMed Ryo A, Hirai A, Nishi M, Liou YC, Perrem K, Lin SC, Hirano H, Lee SW, Aoki I: A suppressive role of the prolyl isomerase Pin1 in cellular apoptosis mediated by the death-associated protein Daxx. J Biol Chem. 2007, 282: 36671-36681. 10.1074/jbc.M704145200.CrossRefPubMed
17.
go back to reference Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, De Wilde RF, Maitra A, Hicks J, Demarzo AM, Shi C, Sharma R, Laheru D, Edil BH, Wolfgang CL, Schulick RD, Hruban RH, Tang LH, Klimstra DS, Iacobuzio-Donahue C: Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012, 36: 173-184. 10.1097/PAS.0b013e3182417d36.PubMedCentralCrossRefPubMed Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, De Wilde RF, Maitra A, Hicks J, Demarzo AM, Shi C, Sharma R, Laheru D, Edil BH, Wolfgang CL, Schulick RD, Hruban RH, Tang LH, Klimstra DS, Iacobuzio-Donahue C: Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012, 36: 173-184. 10.1097/PAS.0b013e3182417d36.PubMedCentralCrossRefPubMed
18.
go back to reference Zhang H, He J, Li J, Tian D, Gu L, Zhou M: Methylation of RASSF1A gene promoter is regulated by p53 and DAXX. FASEB J. 2013, 27: 232-242. 10.1096/fj.12-215491.PubMedCentralCrossRefPubMed Zhang H, He J, Li J, Tian D, Gu L, Zhou M: Methylation of RASSF1A gene promoter is regulated by p53 and DAXX. FASEB J. 2013, 27: 232-242. 10.1096/fj.12-215491.PubMedCentralCrossRefPubMed
19.
go back to reference Klose RJ, Bird AP: Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006, 31: 89-97. 10.1016/j.tibs.2005.12.008.CrossRefPubMed Klose RJ, Bird AP: Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006, 31: 89-97. 10.1016/j.tibs.2005.12.008.CrossRefPubMed
20.
go back to reference Herranz M, Esteller M: DNA methylation and histone modifications in patients with cancer: potential prognostic and therapeutic targets. Methods Mol Biol. 2007, 361: 25-62.PubMed Herranz M, Esteller M: DNA methylation and histone modifications in patients with cancer: potential prognostic and therapeutic targets. Methods Mol Biol. 2007, 361: 25-62.PubMed
21.
go back to reference Rundlett SE, Carmen AA, Suka N, Turner BM, Grunstein M: Transcriptional repression by UME6 involves deacetylation of lysine 5 of histone H4 by RPD3. Nature. 1998, 392: 831-835. 10.1038/33952.CrossRefPubMed Rundlett SE, Carmen AA, Suka N, Turner BM, Grunstein M: Transcriptional repression by UME6 involves deacetylation of lysine 5 of histone H4 by RPD3. Nature. 1998, 392: 831-835. 10.1038/33952.CrossRefPubMed
22.
go back to reference Vogelauer M, Wu J, Suka N, Grunstein M: Global histone acetylation and deacetylation in yeast. Nature. 2000, 408: 495-498. 10.1038/35044127.CrossRefPubMed Vogelauer M, Wu J, Suka N, Grunstein M: Global histone acetylation and deacetylation in yeast. Nature. 2000, 408: 495-498. 10.1038/35044127.CrossRefPubMed
Metadata
Title
Immunohistochemical analysis of chromatin remodeler DAXX in high grade urothelial carcinoma
Authors
Antonio Zizzi
Maria Alessandra Montironi
Roberta Mazzucchelli
Marina Scarpelli
Antonio Lopez-Beltran
Liang Cheng
Nicola Paone
Paolo Castellini
Rodolfo Montironi
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2013
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/1746-1596-8-111

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