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Papillomavirus type 16 E6/E7 and human telomerase reverse transcriptase in esophageal cell immortalization and early transformation

Zhang, Hao; Jin, Yuesheng LU ; Chen, Xuehua; Jin, Charlotte LU ; Law, Simon; Tsao, Sai-Wah and Kwong, Yok-Lam (2007) In Cancer Letters 245(1-2). p.184-194
Abstract
Infection with high-risk human papillomavirus (HPV) has been implicated in the pathogenesis of esophageal squamous cell carcinoma, and up-regulation of telomerase in esophageal adenocarcinoma. We immortalized normal esophageal epithelial cells by over-expression of the HPV16 E6/E7 and human telomerase reverse transcriptase (hTERT) genes. HPV16 E6/E7-induced immortalization was accompanied by reduced RB and p53, but increased p16 and p21, protein expression. hTERT-immortalized cells had unaffected RB and p53, but significantly decreased p16 and p21, protein expression. Aurora-A protein was also upregulated in E6E7 immortalized cells, and to a less extent in hTERT immortalized cells. Fluorescence in situ hybridization showed that the... (More)
Infection with high-risk human papillomavirus (HPV) has been implicated in the pathogenesis of esophageal squamous cell carcinoma, and up-regulation of telomerase in esophageal adenocarcinoma. We immortalized normal esophageal epithelial cells by over-expression of the HPV16 E6/E7 and human telomerase reverse transcriptase (hTERT) genes. HPV16 E6/E7-induced immortalization was accompanied by reduced RB and p53, but increased p16 and p21, protein expression. hTERT-immortalized cells had unaffected RB and p53, but significantly decreased p16 and p21, protein expression. Aurora-A protein was also upregulated in E6E7 immortalized cells, and to a less extent in hTERT immortalized cells. Fluorescence in situ hybridization showed that the Aurora-A gene locus was amplified in E6E7 immortalized cells, which might account in part for the Aurora-A overexpression. These molecular changes led to an abrogation of the G2 checkpoint. E6E7 and hTERT immortalized esophageal cells recapitulated many of the molecular changes observed in esophageal carcinomas, where RB and p53 are frequently downregulated. However, down-regulation of p16 and p21 occurred frequently in esophageal cancer, owing to aberrant gene promoter methylation. We showed in the immortalized cells that aberrant methylation had not yet set in, suggesting that promoter methylation might not be necessary for cellular immortalization. In addition to supporting the role of HPV and telomerase in esophageal carcinogenesis, our cell lines may also be useful in vitro models for further studies of esophageal carcinogenesis. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
esophageal cancer, HPV, telomerase
in
Cancer Letters
volume
245
issue
1-2
pages
184 - 194
publisher
Elsevier
external identifiers
  • wos:000244146100023
  • scopus:33845751069
ISSN
1872-7980
DOI
10.1016/j.canlet.2006.01.005
language
English
LU publication?
yes
id
5ac0b6c4-5435-40ec-aad7-e26ee72e2e15 (old id 674771)
date added to LUP
2007-12-19 11:52:39
date last changed
2017-01-01 07:28:24
@article{5ac0b6c4-5435-40ec-aad7-e26ee72e2e15,
  abstract     = {Infection with high-risk human papillomavirus (HPV) has been implicated in the pathogenesis of esophageal squamous cell carcinoma, and up-regulation of telomerase in esophageal adenocarcinoma. We immortalized normal esophageal epithelial cells by over-expression of the HPV16 E6/E7 and human telomerase reverse transcriptase (hTERT) genes. HPV16 E6/E7-induced immortalization was accompanied by reduced RB and p53, but increased p16 and p21, protein expression. hTERT-immortalized cells had unaffected RB and p53, but significantly decreased p16 and p21, protein expression. Aurora-A protein was also upregulated in E6E7 immortalized cells, and to a less extent in hTERT immortalized cells. Fluorescence in situ hybridization showed that the Aurora-A gene locus was amplified in E6E7 immortalized cells, which might account in part for the Aurora-A overexpression. These molecular changes led to an abrogation of the G2 checkpoint. E6E7 and hTERT immortalized esophageal cells recapitulated many of the molecular changes observed in esophageal carcinomas, where RB and p53 are frequently downregulated. However, down-regulation of p16 and p21 occurred frequently in esophageal cancer, owing to aberrant gene promoter methylation. We showed in the immortalized cells that aberrant methylation had not yet set in, suggesting that promoter methylation might not be necessary for cellular immortalization. In addition to supporting the role of HPV and telomerase in esophageal carcinogenesis, our cell lines may also be useful in vitro models for further studies of esophageal carcinogenesis.},
  author       = {Zhang, Hao and Jin, Yuesheng and Chen, Xuehua and Jin, Charlotte and Law, Simon and Tsao, Sai-Wah and Kwong, Yok-Lam},
  issn         = {1872-7980},
  keyword      = {esophageal cancer,HPV,telomerase},
  language     = {eng},
  number       = {1-2},
  pages        = {184--194},
  publisher    = {Elsevier},
  series       = {Cancer Letters},
  title        = {Papillomavirus type 16 E6/E7 and human telomerase reverse transcriptase in esophageal cell immortalization and early transformation},
  url          = {http://dx.doi.org/10.1016/j.canlet.2006.01.005},
  volume       = {245},
  year         = {2007},
}