Human homologue for Caenorhabditis elegans CUL-4 protein overexpression is associated with malignant potential of epithelial ovarian tumours and poor outcome in carcinoma
- Peter Birner1,
- Alexandra Schoppmann2,
- Monika Schindl3,
- Carina Dinhof4,
- Bettina Jesch4,
- Anna Sophie Berghoff4,5,
- Sebastian F Schoppmann4
- 1Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
- 2Department of Anesthesiology, Medical University of Vienna, Vienna, Austria
- 3Department of Gynecology and Obstetrics, Landesklinikum St Pölten, St Pölten, Austria
- 4Department of Surgery, Medical University of Vienna, Vienna, Austria
- 5Institute of Neurology, Medical University of Vienna, Vienna, Austria
- Correspondence to Professor Sebastian F Schoppmann, Department of Surgery, University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria; sebastian.schoppmann{at}meduniwien.ac.at
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Contributors PB: conception and design, analysis and interpretation of data, drafting the article, final approval of the version to be published. AS: analysis and interpretation of data, drafting the article, final approval of the version to be published. MS: idea for the study, collection of clinical data, analysis of data, drafting the article, final approval of the version to be published. CD: conception and design, analysis and interpretation of data, drafting the article, final approval of the version to be published. BJ: collection of tissue samples and technical work, drafting the article, final approval of the version to be published. ASB: conception and design, analysis and interpretation of data, drafting the article, final approval of the version to be published. SFS: conception and design, analysis and interpretation of data, revising it critically for important intellectual content, drafting of the article, final approval of the version to be published.
- Accepted 7 February 2012
- Published Online First 23 March 2012
Abstract
Background CUL-4 plays a critical role in DNA replication in Caenorhabditis elegans, and interacts with p53 and p21 proteins in cell cycle regulation and response to genomic instability. However, the role of CUL-4 in human carcinomas is widely unknown.
Aims To investigate the expression of CUL-4 protein and its association with p53 and p21, and to determine its prognostic relevance in invasive ovarian carcinoma.
Methods CUL-4, p53 and p21 protein expression was determined retrospectively by immunohistochemistry in 140 specimens of human epithelial ovarian tumours (98 invasive carcinomas and 42 tumours of low malignant potential; LMP).
Results Overexpression of CUL-4 was observed in 41 (41.8%) of carcinoma samples and in 10 (23.8%) LMP tumours. CUL-4 was significantly more often overexpressed in invasive carcinomas compared with LMP tumours (p=0.042, χ2 test, OR 2.302, 95% CI 1.018 to 5.203). In invasive carcinoma, CUL-4 overexpression was found to be a prognostic factor for overall (p=0.017, Cox regression, HR 2.387, 95% CI 1.17 to 4.869) and disease-free survival (p=0.005, Cox regression, HR 3.5, 95% CI 1.465 to 8.365), respectively. In subgroup analysis, CUL-4 was only of prognostic relevance in carcinomas without p53 expression.
Conclusion These data indicate for the first time that CUL-4 might play a relevant role in the development and progression of ovarian carcinoma, warranting further investigations. Degradation of wild-type p53 might be a key mechanism to explain why CUL-4 leads to more aggressive clinical behaviour. Not only CUL-4 itself, but also its associated proteins might represent targets for novel, selective therapeutic strategies.
Footnotes
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Competing interests None.
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Patient consent Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
