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Transcriptional upregulation and unmethylation of the promoter region of p16 in invasive basal cell carcinoma cells and partial co-localization with the gamma2 chain of laminin-332.

Svensson Månsson, Sofie LU ; Reis-Filho, J and Landberg, Göran LU (2007) In Journal of Pathology 212(1). p.102-111
Abstract
Basal cell carcinoma cells show low proliferation rates at the invasive front and a concordant upregulation of the cdk-inhibitor p16, limiting proliferative capacity. Little is known about the mechanisms of p16 regulation in normal and malignant cells apart from that many transcription factors such as Ets1, Ets2, SP1, SP3, JunB and the polycomb protein Bmi1 have the potential to induce or repress p16 expression. Therefore, the aim of this study was to determine how p16 is regulated in basal cell carcinoma with special focus on its upregulation in invasive cells. By analysing various microdissected areas of basal cell carcinoma using real-time quantitative PCR we observed upregulation of p16 mRNA in invasive tumour cells compared to... (More)
Basal cell carcinoma cells show low proliferation rates at the invasive front and a concordant upregulation of the cdk-inhibitor p16, limiting proliferative capacity. Little is known about the mechanisms of p16 regulation in normal and malignant cells apart from that many transcription factors such as Ets1, Ets2, SP1, SP3, JunB and the polycomb protein Bmi1 have the potential to induce or repress p16 expression. Therefore, the aim of this study was to determine how p16 is regulated in basal cell carcinoma with special focus on its upregulation in invasive cells. By analysing various microdissected areas of basal cell carcinoma using real-time quantitative PCR we observed upregulation of p16 mRNA in invasive tumour cells compared to centrally localized tumour cells. The methylation status of the p16 promoter, analysed by methylation-specific PCR, also showed diminished methylation in tumour cells at the invasive front, supporting the hypothesis that promoter methylation can affect the transcriptional activation of p16 in vivo. There was only sporadic co-localization of Ets, or ERK1/2 phosphorylation with p16 upregulation at the invasive front, suggesting that these factors were not directly involved in the regulation of p16. Furthermore, the gamma 2 chain of laminin-332 has been reported to be increased at the invasive front compared to the central areas of many tumours. Interestingly, in basal cell carcinoma we observed partial co-localization between p16 and the gamma 2 chain of laminin-332 in tumour cells towards areas of ulceration and in the majority of clearly infiltrative tumour cells but not in p16 positive tumour cells with a more pushing invasive growth pattern. These data suggest that concurrent p16 upregulation and decreased proliferation are more general phenomena in different types of invasive growth patterns in basal cell carcinomas and that these only partially overlap with the gamma 2 chain of laminin-332 associated invasion patterns. Copyright (C) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
p16, laminin-332 gamma 2, ERK, Ets, LCM, MSP-PCR, RTQ-PCR, basal cell carcinoma
in
Journal of Pathology
volume
212
issue
1
pages
102 - 111
publisher
John Wiley & Sons
external identifiers
  • wos:000246415200012
  • scopus:34248577470
ISSN
0022-3417
DOI
10.1002/path.2152
language
English
LU publication?
yes
id
929ee826-7026-4b27-aeb7-5fd5330be5f5 (old id 166383)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17370299&dopt=Abstract
date added to LUP
2007-07-27 10:53:16
date last changed
2017-01-01 04:49:44
@article{929ee826-7026-4b27-aeb7-5fd5330be5f5,
  abstract     = {Basal cell carcinoma cells show low proliferation rates at the invasive front and a concordant upregulation of the cdk-inhibitor p16, limiting proliferative capacity. Little is known about the mechanisms of p16 regulation in normal and malignant cells apart from that many transcription factors such as Ets1, Ets2, SP1, SP3, JunB and the polycomb protein Bmi1 have the potential to induce or repress p16 expression. Therefore, the aim of this study was to determine how p16 is regulated in basal cell carcinoma with special focus on its upregulation in invasive cells. By analysing various microdissected areas of basal cell carcinoma using real-time quantitative PCR we observed upregulation of p16 mRNA in invasive tumour cells compared to centrally localized tumour cells. The methylation status of the p16 promoter, analysed by methylation-specific PCR, also showed diminished methylation in tumour cells at the invasive front, supporting the hypothesis that promoter methylation can affect the transcriptional activation of p16 in vivo. There was only sporadic co-localization of Ets, or ERK1/2 phosphorylation with p16 upregulation at the invasive front, suggesting that these factors were not directly involved in the regulation of p16. Furthermore, the gamma 2 chain of laminin-332 has been reported to be increased at the invasive front compared to the central areas of many tumours. Interestingly, in basal cell carcinoma we observed partial co-localization between p16 and the gamma 2 chain of laminin-332 in tumour cells towards areas of ulceration and in the majority of clearly infiltrative tumour cells but not in p16 positive tumour cells with a more pushing invasive growth pattern. These data suggest that concurrent p16 upregulation and decreased proliferation are more general phenomena in different types of invasive growth patterns in basal cell carcinomas and that these only partially overlap with the gamma 2 chain of laminin-332 associated invasion patterns. Copyright (C) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.},
  author       = {Svensson Månsson, Sofie and Reis-Filho, J and Landberg, Göran},
  issn         = {0022-3417},
  keyword      = {p16,laminin-332 gamma 2,ERK,Ets,LCM,MSP-PCR,RTQ-PCR,basal cell carcinoma},
  language     = {eng},
  number       = {1},
  pages        = {102--111},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Pathology},
  title        = {Transcriptional upregulation and unmethylation of the promoter region of p16 in invasive basal cell carcinoma cells and partial co-localization with the gamma2 chain of laminin-332.},
  url          = {http://dx.doi.org/10.1002/path.2152},
  volume       = {212},
  year         = {2007},
}