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Smad4 deficiency in cervical carcinoma cells

Oncogene volume 24, pages 810–819 (2005)Cite this article

Abstract

Squamous cell carcinoma of the uterine cervix is one of the most frequent cancers affecting women worldwide. Carcinomas arise from cervical intraepithelial lesions, in which infection with high-risk human papillomavirus types has led to deregulated growth control through the actions of the viral E6 and E7 oncoproteins. The molecular mechanisms underlying progression to invasive tumor growth are poorly understood. One important feature, however, is the escape from growth inhibition by transforming growth factor β (TGF-β). Loss of chromosomal arm 18q is among the most frequent cytogenetic alterations in cervical cancers and has been associated with poor prognosis. Since the TGF-β response is mediated by Smad proteins and the tumor suppressor gene Smad4 resides at 18q21, we have analysed the Smad4 gene for cervical cancer-associated alterations in cell lines and primary carcinomas. Here, we report Smad4 deficiency in four out of 13 cervical cancer cell lines which is due to an intronic rearrangement or deletions of 3′ exons. All cell lines, however, showed either absent or moderate responsiveness to TGF-β irrespective of their Smad4 status. In 41 primary squamous cervical carcinomas analysed, 10 samples showed loss of Smad4 protein expression and 26 samples a reduced expression. Altogether, our results strongly suggest that Smad4 gene alterations are involved in cervical carcinogenesis.

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Acknowledgements

We thank A Baar; C Eilert-Micus and M Becker for excellent technical assistance and A Hunzicker for DNA sequence analysis. This work was supported by grants from the Deutsche Krebshilfe – Dr Mildred Scheel-Stiftung (to WHS and IS-W) and the Cologne Fortune Program (to SEB).

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Author notes

  1. Stephan E Baldus and Elisabeth Schwarz: These two authors contributed equally to this work

Authors and Affiliations

  1. Institute of Pathology, University of Cologne, D-50931, Cologne, Germany

    Stephan E Baldus, Stephanie Landsberg & Hans Peter Dienes

  2. German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany

    Elisabeth Schwarz & Claudia Lohrey

  3. Institute of Pathology, D-68159, Mannheim, Germany

    Dietmar Schmidt

  4. Department of Internal Medicine, Knappschafts-Krankenhaus, University of Bochum, D-44892, Bochum, Germany

    Marc Zapatka, Stephan A Hahn, Wolff H Schmiegel & Irmgard Schwarte-Waldhoff

  5. Department of Gastroenterology and Hepatology, Bergmannsheil, University of Bochum, D-44892, Bochum, Germany

    Wolff H Schmiegel

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  1. Stephan E Baldus
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Correspondence to Irmgard Schwarte-Waldhoff.

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Baldus, S., Schwarz, E., Lohrey, C. et al. Smad4 deficiency in cervical carcinoma cells. Oncogene 24, 810–819 (2005). https://doi.org/10.1038/sj.onc.1208235

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