Alteration of the MDM2-p73-P14ARF pathway related to tumour progression during urinary bladder carcinogenesis

  • Authors:
    • Thilo Schlott
    • Thomas Quentin
    • Monika Korabiowska
    • Bettina Budd
    • Ekkehard Kunze
  • View Affiliations

  • Published online on: November 1, 2004     https://doi.org/10.3892/ijmm.14.5.825
  • Pages: 825-836
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Transitional cell carcinomas (TCC) of the urinary bladder develop by a multistep process characterized by various stages of transformation differing in their grade of malignancy and biological behaviour. Since the prospective clinical outcome cannot be reliably predicted on histopathological grounds, we analysed the mRNA expression of the MDM2-p73-P14ARF tumour surveillance pathway in an attempt to detect alterations of gene activity, allowing a better understanding of the mechanisms responsible for conversion of low to high malignant TCC. Expression of the mRNA was determined in 71 TCC of various grades and stages using the real-time quantitative reverse transcription-polymerase chain reaction. The MDM2-p73-P14ARF pathway was dominated by the MDM2 gene, the mRNA expression of which proved to be significantly (5-fold) lower in advanced high-grade, high-stage than in superficial low-grade, low-stage TCC. Conversely, the expression of p73 mRNA increased with increasing tumour grades and stages, while the activity of the P14ARF gene was not substantially altered during early and late phases of urothelial carcinogenesis. Analysing the expression of spliced variants of MDM2 mRNA, we found a heterogeneous pattern including a novel splicing transcript coding for an abnormal protein. Promoter hypermethylation of P14ARF occurred in 10% of the TCC with an under-expression of mRNA. An analysis of the effects of lifestyle and occupational bladder cancer risk factors revealed that TCC of smokers showed a 2-fold elevated expression of MDM2 mRNA and an approximately 2-fold lower expression of P14ARF mRNA, whereas the activity of the p73 gene was unchanged. Heavy coffee consumption was associated with a 2-fold decreased expression level of P14ARF mRNA. Exposure to certain occupational hazards (plastic products, paints and lacquer, polycyclic hydrocarbons, chemical solvents) was observed to modulate the activity of the genes analysed. Our findings suggest that an alteration in the MDM2-p73-P14ARF pathway is involved in the progression of bladder cancer to a more malignant and aggressive form.

Related Articles

Journal Cover

November 2004
Volume 14 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Schlott T, Quentin T, Korabiowska M, Budd B and Kunze E: Alteration of the MDM2-p73-P14ARF pathway related to tumour progression during urinary bladder carcinogenesis. Int J Mol Med 14: 825-836, 2004
APA
Schlott, T., Quentin, T., Korabiowska, M., Budd, B., & Kunze, E. (2004). Alteration of the MDM2-p73-P14ARF pathway related to tumour progression during urinary bladder carcinogenesis. International Journal of Molecular Medicine, 14, 825-836. https://doi.org/10.3892/ijmm.14.5.825
MLA
Schlott, T., Quentin, T., Korabiowska, M., Budd, B., Kunze, E."Alteration of the MDM2-p73-P14ARF pathway related to tumour progression during urinary bladder carcinogenesis". International Journal of Molecular Medicine 14.5 (2004): 825-836.
Chicago
Schlott, T., Quentin, T., Korabiowska, M., Budd, B., Kunze, E."Alteration of the MDM2-p73-P14ARF pathway related to tumour progression during urinary bladder carcinogenesis". International Journal of Molecular Medicine 14, no. 5 (2004): 825-836. https://doi.org/10.3892/ijmm.14.5.825