Carcinogenesis Advance Access published online on May 9, 2003
Carcinogenesis, doi:10.1093/carcin/bgg070
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Division of Molecular Genetics, Institute of Biomedical and Life Sciences, University of Glasgow, 54 Dumbarton Road, Glasgow G11 6NU, UK
* Corresponding author. E-mail: joanna.wilson{at}bio.gla.ac.uk.
Received 24 December 2002
; revised 20 March 2003
; accepted 16 April 2003
Nasopharyngeal carcinoma (NPC) is the most tightly Epstein-Barr virus (EBV) associated tumour. The EBV oncoprotein latent membrane protein-1 (LMP1) is frequently expressed in NPC tumours and may play a role in the genesis of the disease. NPC tumours often exhibit loss of expression (by deletion or methylation) of the INK4a locus, which encodes the tumour suppressor genes p16INK4a and p14ARF. To investigate the contribution of LMP1 and INK4a loss in tumourigenesis, skin chemical carcinogenesis was conducted using PyLMP1 and INK4a null mice. Surprisingly, INK4a null mice developed significantly fewer papillomas than wild type mice, nevertheless, the papillomas that did develop grew faster and converted more rapidly to carcinoma than controls. This indicates that while loss of the INK4a locus plays an important role at the later stages of tumourigenesis, initially its loss inhibits papilloma formation. Conversely, LMP1 promoted papilloma formation but paradoxically inhibited papilloma growth. Using cross breeds, it was found that LMP1 cooperates with loss of the INK4a locus during epithelial tumourigenesis. The expression of LMP1 overcame the inhibition in papilloma formation observed in INK4a null mice, whilst the loss of the INK4a locus counteracted the inhibition in papilloma growth rate found in PyLMP1 mice. This suggests that LMP1 mediates the inhibition in papilloma growth via one or both of the INK4a locus products. Intriguingly, mice heterozygous for INK4a loss showed lesion growth rates intermediate between wild type and null, demonstrative of haploinsufficiency. We propose that LMP1 acts at the early stages in carcinogenesis to promote the development of benign tumours and that early reduction of INK4a locus expression allows these lesions to expand in size. In addition, loss of the INK4a locus accelerates the development of a more aggressive lesion. Conversely, complete loss of the INK4a locus in an otherwise normal cell might inhibit lesion formation.
chemical carcinogenesis, EBV, INK4a, LMP1, NPC, p16, p19
The latent membrane protein 1 of epstein-barr virus and loss of the INK4a locus: paradoxes resolve to cooperation in carcinogenesis in vivo
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