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HPV Integration bei Kopf-Hals-KarzinomenIntegrstion of HPV in Head and Neck Cancer

Integration of HPV in Head and Neck Cancer

During the progression of a persistant HPV16 infection, proliferating cells of the lower epithelial layers start to express viral genes. Replication of the viral genome still occures as extrachromosomal circular episomes, whereupon the expression of HPV-genes highly rushes. This effects especially the oncogenes E6 and E7. They bind and degrade p53 and Rb, respectively. This leads to a massive deregulation of the host-cell DNA synthesis and loss of cell cyle control with rising instability of the host genome 1-3. The consequences are abnormal centrosome numbers, misssegregations, and aneuploidies 1. But for the transition from dysplasia to invasive cancer integration of the viral DNA into the cellular host genome is needed. Therefore, the open reading frame of the viral E1/E2 region is disrupted and nonhomologous sequence-specific recombination at a single or a few chromosomal loci occures. Subsequently the internal viral transcription control of E6 and E7 gets lost so that their effects are increased 4,5. Furthermore, the integration results in the loss of the polyadenylation signal of genes in the E4 region. This leads to the formation of viral-cellular fusiontranskripts. Through the loss of AU-rich, mRNA-destabilising sequences in the 3’-LCR E6- and E7-fusiontranscripts are more stabile than episomal ocogenetranscripts 6. Even more, the direct context of the genomic integration site seems to influence the activity of the viral oncogeneexpression 2. In cervical carcinomas, integration sites are distributed through the whole genome and differ from clinical sample to sample 3,7. The involvmet of specific integration sites like the paradigm of the retroviral insertionmutagenesis can be excluded 8.

On the other hand, the HP-Virus shows a targeted deaktivation of cell cycle regulation. The viral oncogene E6 binds to p53 and degrades it, so that apoptosis induction is avoided. Oncoprotein E7 binds to retinoblastoma protein b (pRb) and subsequentially inactivates cell cycle control with unregulated cell cycle activity. Furthermore, E6 and E7 disrupt the regulation of the mitotic spindle apparatus. This leads to mistakes in seggregation of chromosomes, with broken, numeric and structural chromosome abnormalities, as well as inbalances of allels 9. Hence, they are not as pronounced as in HPV-negative HNSCC 10. The chromosomal instability is therefore an outstanding event in the development of HPV-induced tumors.

 

 

 

1.        Duensing, S. et al. The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle. Proc Natl Acad Sci USA 97, 10002–10007 (2000).

2.        Knebel Doeberitz, von, M., Bauknecht, T., Bartsch, D. & Hausen, zur, H. Influence of chromosomal integration on glucocorticoid-regulated transcription of growth-stimulating papillomavirus genes E6 and E7 in cervical carcinoma cells. Proc Natl Acad Sci USA 88, 1411–1415 (1991).

3.        Luft, F. et al. Detection of integrated papillomavirus sequences by ligation-mediated PCR (DIPS-PCR) and molecular characterization in cervical cancer cells. Int J Cancer 92, 9–17 (2001).

4.        Kessis, T. D., Connolly, D. C., Hedrick, L. & Cho, K. R. Expression of HPV16 E6 or E7 increases integration of foreign DNA. Oncogene 13, 427–431 (1996).

5.        Romanczuk, H. & Howley, P. M. Disruption of either the E1 or the E2 regulatory gene of human papillomavirus type 16 increases viral immortalization capacity. Proc Natl Acad Sci USA 89, 3159–3163 (1992).

6.        Jeon, S. & Lambert, P. F. Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis. Proc Natl Acad Sci USA 92, 1654–1658 (1995).

7.        Wentzensen, N., Vinokurova, S. & Knebel Doeberitz, von, M. Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. 64, 3878–3884 (2004).

8.        Butel, J. S. Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis 21, 405–426 (2000).

9.        Thomas, J. T. & Laimins, L. A. Human papillomavirus oncoproteins E6 and E7 independently abrogate the mitotic spindle checkpoint. J Virol 72, 1131–1137 (1998).

10.     Klussmann, J. P. et al. Genetic signatures of HPV-related and unrelated oropharyngeal carcinoma and their prognostic implications. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 15, 1779–1786 (2009).


Idientified HPV16 integration sites



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