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Down-regulation of Ku 70 and Ku 80 mRNA expression in transitional cell carcinomas of the urinary bladder related to tumor progression

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Abstract

DNA-dependent protein kinase (DNA-PK) containing the regulatory subunits Ku 70 and Ku 80 plays a prominent role in the repair of double-stranded DNA breaks by a nonhomologous end-joining pathway maintaining genomic stability. In an attempt to elucidate the significance of the DNA-PK complex for human urothelial carcinogenesis, the expression of Ku 70 and Ku 80 was studied in 71 transitional cell carcinomas (TCC) of the urinary bladder of various grades and stages, and in relation to lifestyle and occupational bladder cancer risk factors. To analyse the mRNA expression of Ku 70 and Ku 80, real-time quantitative reverse transcription-polymerase chain reaction was used and the protein expression assessed by immunohistochemistry. Advanced high-grade, high-stage TCC expressed the mRNA of Ku 70 and Ku 80 at a lower level than superficial low-grade, low-stage carcinomas, suggesting down-regulation of the Ku system to be associated with progression of bladder cancer from a low to a high malignant potential. The protein expression of Ku 70 and Ku 80 was closely related and decreased consistently with increasing grades and stages, paralleling the expression of the mRNA. Among hazardous environmental bladder cancer risk factors, heavy consumption of coffee was associated with a twofold decreased Ku 70 and Ku 80 mRNA expression, whereas tobacco smoke did not substantially affect the activity of the Ku system, except for a trend towards a dose-response relationship in the expression of Ku 70 mRNA. There is some evidence that exposure to polycyclic hydrocarbons, paints and lacquer, and stone dust may modify the expression of Ku 70 mRNA. Although the underlying molecular genetic pathways are not yet clearly understood, our data indicate that down-regulation of the Ku system promotes progression of urothelial carcinogenesis to a more malignant and aggressive clinical behavior, presumably as a result of an impaired capacity for DNA repair.

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Acknowledgements

This work was supported by the Else Kröner-Fresenius Foundation, Bad Homburg v.d. Höhe, Germany (grant numbers 1344170 and 1344660). The authors thank Prof. Dr. R.-H. Ringert, Department of Urology, University of Göttingen, Dr. H. Bartels, Department of Urology, Evangelisches Krankenhaus Göttingen-Weende and Prof. Dr. M. Blech, Kreiskrankenhaus Northeim, for supplying fresh tumor tissue and allowing us to interview their patients. The authors also wish to express their gratitude to Dipl. Ing. S. Kellner for performing the statistical analysis and to Miss B. Jünemann for excellent technical processing of the immunohistochemical staining.

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Authors and Affiliations

  1. Department of Cytopathology, Center of Pathology, University of Göttingen, Germany

    Monika Korabiowska, Thilo Schlott & Hanne Bauer

  2. Department of Osteopathology and Hematology, Center of Pathology, University of Göttingen, Robert-Koch-Straße 40, 37075 Göttingen

    Thomas Quentin & Ekkehard Kunze

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  1. Monika Korabiowska
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Correspondence to Ekkehard Kunze.

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Korabiowska, M., Quentin, T., Schlott, T. et al. Down-regulation of Ku 70 and Ku 80 mRNA expression in transitional cell carcinomas of the urinary bladder related to tumor progression. World J Urol 22, 431–440 (2004). https://doi.org/10.1007/s00345-004-0453-5

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