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Human homologue for Caenorhabditis elegans CUL-4 protein overexpression is associated with malignant potential of epithelial ovarian tumours and poor outcome in carcinoma
  1. Peter Birner1,
  2. Alexandra Schoppmann2,
  3. Monika Schindl3,
  4. Carina Dinhof4,
  5. Bettina Jesch4,
  6. Anna Sophie Berghoff4,5,
  7. Sebastian F Schoppmann4
  1. 1Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
  2. 2Department of Anesthesiology, Medical University of Vienna, Vienna, Austria
  3. 3Department of Gynecology and Obstetrics, Landesklinikum St Pölten, St Pölten, Austria
  4. 4Department of Surgery, Medical University of Vienna, Vienna, Austria
  5. 5Institute of Neurology, Medical University of Vienna, Vienna, Austria
  1. 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

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.

  • Caenorhabditis elegans
  • cancer
  • CUL-4
  • gastric
  • gastric cancer
  • ovarian carcinoma
  • p53
  • prognosis
  • survival

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Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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