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Cellular Oncology
Volume 30 (2008), Issue 1, Pages 77-87
http://dx.doi.org/10.1155/2008/279656

Alterations in AP-1 and AP-1 Regulatory Genes during HPV-Induced Carcinogenesis

Jillian de Wilde,1 Johanna De-Castro Arce,2 Peter J. F. Snijders,1 Chris J. L. M. Meijer,1 Frank Rösl,2 and Renske D. M. Steenbergen1

1Department of Pathology, Unit of Molecular Pathology, VU University Medical Center, Amsterdam, The Netherlands
2Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Heidelberg, Germany

Copyright © 2008 Hindawi Publishing Corporation and the authors. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background: Previous studies demonstrated a functional involvement of the AP-1 transcription factor in HPV-induced cervical carcinogenesis. Here, we aimed to obtain further insight in expression alterations of AP-1 family members during HPV-mediated transformation and their relationship to potential regulatory (Notch1, Net) and target (CADM1) genes.

Methods: mRNA expression levels of c-Jun, JunB, junD, c-Fos, FosB, Fra-1, Fra-2, Notch1, Net and CADM1 were determined by quantitative RT-PCR in primary keratinocytes (n=5), early (n=4) and late (n=4) passages of non-tumorigenic HPV-immortalized keratinocytes and in tumorigenic cervical cancer cell lines (n=7). In a subset of cell lines protein expression and AP-1 complex composition was determined.

Results: Starting in immortal stages c-Fos, Fra-2 and JunB expression became up regulated towards tumorigenicity, whereas Fra-1, c-Jun, Notch1, Net and CADM1 became down regulated. The onset of deregulated expression varied amongst the AP-1 members and was not directly related to altered Notch1, Net or CADM1 expression. Nevertheless, a shift in AP-1 complex composition from Fra-1/c-Jun to c-Fos/c-Jun heterodimers was only observed in tumorigenic cells.

Conclusion: HPV-mediated transformation is associated with altered AP-1, Notch1, Net and CADM1 transcription. Whereas the onset of deregulated expression of various AP-1 family members became already manifest during the immortal state, a shift in AP-1 complex composition appeared a rather late event associated with tumorigenicity.