Alterations in AP-1 and AP-1 regulatory genes during HPV-induced carcinogenesis

Jillian De Wilde, Johanna De-Castro Arce, Peter J.F. Snijders, Chris J.L.M. Meijer, Frank Rösl, Renske D.M. Steenbergen

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)77-87
Number of pages11
JournalCellular Oncology
Volume30
Issue number1
StatePublished - Feb 1 2008

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Transcription Factor AP-1
Regulator Genes
Carcinogenesis
Keratinocytes
Cell Line
Uterine Cervical Neoplasms
Polymerase Chain Reaction
Messenger RNA
Genes

Keywords

  • AP-1
  • CADM1
  • Cervical cancer
  • Fra-1
  • HPV
  • Net
  • Notch1
  • c-Fos

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

Cite this

De Wilde, J., De-Castro Arce, J., Snijders, P. J. F., Meijer, C. J. L. M., Rösl, F., & Steenbergen, R. D. M. (2008). Alterations in AP-1 and AP-1 regulatory genes during HPV-induced carcinogenesis. Cellular Oncology, 30(1), 77-87.

Alterations in AP-1 and AP-1 regulatory genes during HPV-induced carcinogenesis. / De Wilde, Jillian; De-Castro Arce, Johanna; Snijders, Peter J.F.; Meijer, Chris J.L.M.; Rösl, Frank; Steenbergen, Renske D.M.

In: Cellular Oncology, Vol. 30, No. 1, 01.02.2008, p. 77-87.

Research output: Contribution to journalArticle

De Wilde, J, De-Castro Arce, J, Snijders, PJF, Meijer, CJLM, Rösl, F & Steenbergen, RDM 2008, 'Alterations in AP-1 and AP-1 regulatory genes during HPV-induced carcinogenesis', Cellular Oncology, vol. 30, no. 1, pp. 77-87.
De Wilde J, De-Castro Arce J, Snijders PJF, Meijer CJLM, Rösl F, Steenbergen RDM. Alterations in AP-1 and AP-1 regulatory genes during HPV-induced carcinogenesis. Cellular Oncology. 2008 Feb 1;30(1):77-87.
De Wilde, Jillian ; De-Castro Arce, Johanna ; Snijders, Peter J.F. ; Meijer, Chris J.L.M. ; Rösl, Frank ; Steenbergen, Renske D.M. / Alterations in AP-1 and AP-1 regulatory genes during HPV-induced carcinogenesis. In: Cellular Oncology. 2008 ; Vol. 30, No. 1. pp. 77-87.
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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.",
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