Epigenetic inactivation of ITIH5 promotes bladder cancer progression and predicts early relapse of pT1 high-grade urothelial tumours

Rose M, Gaisa NT, Antony P, Fiedler D, Heidenreich A, Otto W, Denzinger S, Bertz S, Hartmann A, Karl A, Knüchel R, Dahl E (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Carcinogenesis Oxford University Press (OUP): Policy B - Oxford Open Option B

Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B

Book Volume: 35

Pages Range: 727-36

Journal Issue: 3

DOI: 10.1093/carcin/bgt375

Abstract

Inter-?-trypsin inhibitor heavy chain 5 (ITIH5) has been associated with tumour suppression in various cancers. However, its putative role in bladder cancer is completely unknown. Therefore, we initiated a study analysing ITIH5 expression as well as its prognostic and functional impact on human urothelial cancers (UCs). Expression analysis showed a clear down-regulation of ITIH5 mRNA in 61% (n = 45) of UCs, especially in muscle-invasive tumours (P < 0.001). ITIH5 loss in UCs was further evident on protein level (65.5%, n = 55) as detected by immunohistochemistry. DNA methylation analysis demonstrated tumour-specific ITIH5 promoter methylation in 50% of papillary none-invasive pTa (n = 30) and 68% of invasive (n = 28) UCs. Aberrant ITIH5 promoter methylation in bladder tumours was tightly linked (P < 0.001) with loss of ITIH5 mRNA expression, which was furthermore functionally confirmed by demethylation analysis in cell lines. Pyrosequencing analysis revealed that ITIH5 promoter hypermethylation was closely associated with progressive bladder cancers. Subsequently, a large cohort (n = 120) of clinically challenging pT1 high-grade UC was analysed for ITIH5 expression. Of clinical significance, we found an association between loss of ITIH5 expression and unfavourable prognosis of UC patients without distant metastasis at first diagnosis (recurrence-free survival; hazard ratio: 4.35, P = 0.048). Functionally, ITIH5 re-expression in human RT112 bladder cancer cells led to both suppression of cell migration and inhibition of colony spreading. Hence, we provide evidence that down-regulation of ITIH5 by aberrant DNA hypermethylation may provoke invasive phenotypes in human bladder cancer. Moreover, ITIH5 protein might become a prognostic biomarker for relapse risk stratification in high-grade UC patients.

Authors with CRIS profile

Simone Bertz Institute of Pathology Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie

Involved external institutions

Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE) Universität Regensburg DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE)

How to cite

APA:

Rose, M., Gaisa, N.T., Antony, P., Fiedler, D., Heidenreich, A., Otto, W.,... Dahl, E. (2014). Epigenetic inactivation of ITIH5 promotes bladder cancer progression and predicts early relapse of pT1 high-grade urothelial tumours. Carcinogenesis, 35(3), 727-36. https://doi.org/10.1093/carcin/bgt375

MLA:

Rose, Michael, et al. "Epigenetic inactivation of ITIH5 promotes bladder cancer progression and predicts early relapse of pT1 high-grade urothelial tumours." Carcinogenesis 35.3 (2014): 727-36.

BibTeX: Download