Induction of p16 during immortalization by HPV 16 and 18 and not during malignant transformation

Y. Nakao, X. Yang, M. Yokoyama, A. Ferenczy, Shou-Ching Tang, M. M. Pater, A. Pater

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Abstract

The p16 (MTS1) tumour-suppressor gene is a cyclin-dependent kinase (cdk) inhibitor that decelerates the cell cycle by inactivating the cdks that phosphorylate the retinoblastoma tumour-suppressor gene (Rb) protein (pRb). In cervical cancers, pRb is inactivated by the HPV E7 oncoprotein or by mutations. The hypothesis of earlier reports was that the disruption of the p16/cdk-cyclin/Rb cascade is essential for malignant cervical transformation/carcinogenesis. We previously established in vitro model systems of cervical cancer representing four steps of oncogenic progression initiated by the two most common oncogenic HPVs in ectocervical and endocervical epithelial cells. This report used these systems to investigate the role of p16 in cervical cancers. A dramatic enhancement of the p16 RNA level was observed after immortalization by HPV 16 or 18. Furthermore, the p16 protein was newly observed following immortalization. However, no further changes were found for RNA or protein levels after serum selection or malignant transformation. For three cervical carcinoma cell lines, similar high levels of p16 expression were seen. Point mutations or homozygous deletions of p16 were not observed in the in vitro systems or in clinical specimens. These results suggest that the inactivation of the p16/cdk-cyclin/Rb cascade does not occur during malignant transformation but occurs during the immortalization by HPV in HPV-harbouring premalignant lesions, the in situ equivalent of immortalized cells. Also suggested is that p16 has no role in the specific malignant transformation step from immortal premalignant lesions during the carcinogenesis of HPV-initiated cervical cancers.

Original languageEnglish (US)
Pages (from-to)1410-1416
Number of pages7
JournalBritish Journal of Cancer
Volume75
Issue number10
DOIs
StatePublished - Jan 1 1997

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Keywords

  • Cell cycle
  • Cervical cancer
  • Cyclin-dependent kinase
  • Human papillomavirus
  • Immortalization
  • Retinoblastoma tumour suppressor
  • Transformation
  • p16

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nakao, Y., Yang, X., Yokoyama, M., Ferenczy, A., Tang, S-C., Pater, M. M., & Pater, A. (1997). Induction of p16 during immortalization by HPV 16 and 18 and not during malignant transformation. British Journal of Cancer, 75(10), 1410-1416. https://doi.org/10.1038/bjc.1997.243