Cystatin C Deficiency Promotes Epidermal Dysplasia in K14-HPV16 Transgenic Mice
(2010) In PLoS ONE 5(11).- Abstract
- Background: Cysteine protease cathepsins are important in extracellular matrix protein degradation, cell apoptosis, and angiogenesis. Mice lacking cathepsins are protected from tumor progression in several animal models, suggesting that the regulation of cathepsin activities controls the growth of various malignant tumors. Methods and Results: We tested the role of cathepsins using a mouse model of multistage epithelial carcinogenesis, in which the human keratin-14 promoter/enhancer drove the expression of human papillomavirus type 16 (HPV16) early region E6/E7 transgenes. During the progression of premalignant dysplasia, we observed increased expression of cysteine protease cathepsin S, but concomitantly reduced expression of cathepsin... (More)
- Background: Cysteine protease cathepsins are important in extracellular matrix protein degradation, cell apoptosis, and angiogenesis. Mice lacking cathepsins are protected from tumor progression in several animal models, suggesting that the regulation of cathepsin activities controls the growth of various malignant tumors. Methods and Results: We tested the role of cathepsins using a mouse model of multistage epithelial carcinogenesis, in which the human keratin-14 promoter/enhancer drove the expression of human papillomavirus type 16 (HPV16) early region E6/E7 transgenes. During the progression of premalignant dysplasia, we observed increased expression of cysteine protease cathepsin S, but concomitantly reduced expression of cathepsin endogenous inhibitor cystatin C in the skin tissue extract. Absence of cystatin C in these transgenic mice resulted in more progression of dysplasia to carcinoma in situ on the face, ear, chest, and tail. Chest and ear skin extract real time PCR and immunoblot analysis, mouse serum sample ELISA, tissue immunohistological analysis, and tissue extract-mediated in vitro elastinolysis and collagenolysis assays demonstrated that cystatin C deficiency significantly increased cathepsin expression and activity. In skin from both the chest and ear, we found that the absence of cystatin C reduced epithelial cell apoptosis but increased proliferation. From the same tissue preparations, we detected significantly higher levels of pro-angiogenic laminin 5-derived c2 peptides and concurrently increased neovascularization in cystatin C-deficient mice, compared to those from wild-type control mice. Conclusion: Enhanced cathepsin expression and activity in cystatin C-deficient mice contributed to the progression of dysplasia by altering premalignant tissue epithelial proliferation, apoptosis, and neovascularization. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1752772
- author
- Yu, Weifang
; Liu, Jian
; Shi, Michael A.
; Wang, Jianan
; Xiang, Meixiang
; Kitamoto, Shiro
; Wang, Bing
; Sukhova, Galina K.
; Murphy, George F.
; Orasanu, Gabriela
; Grubb, Anders
LU
and Shi, Guo-Ping
(Less) - organization
- publishing date
- 2010
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS ONE
- volume
- 5
- issue
- 11
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000284231800008
- scopus:78649744423
- pmid:21085595
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0013973
- language
- English
- LU publication?
- yes
- id
- ae5d5cc7-1cdf-4a47-bf75-a97a46da3f5c (old id 1752772)
- date added to LUP
- 2016-04-01 13:20:20
- date last changed
- 2023-01-11 17:55:15
@article{ae5d5cc7-1cdf-4a47-bf75-a97a46da3f5c,
abstract = {{Background: Cysteine protease cathepsins are important in extracellular matrix protein degradation, cell apoptosis, and angiogenesis. Mice lacking cathepsins are protected from tumor progression in several animal models, suggesting that the regulation of cathepsin activities controls the growth of various malignant tumors. Methods and Results: We tested the role of cathepsins using a mouse model of multistage epithelial carcinogenesis, in which the human keratin-14 promoter/enhancer drove the expression of human papillomavirus type 16 (HPV16) early region E6/E7 transgenes. During the progression of premalignant dysplasia, we observed increased expression of cysteine protease cathepsin S, but concomitantly reduced expression of cathepsin endogenous inhibitor cystatin C in the skin tissue extract. Absence of cystatin C in these transgenic mice resulted in more progression of dysplasia to carcinoma in situ on the face, ear, chest, and tail. Chest and ear skin extract real time PCR and immunoblot analysis, mouse serum sample ELISA, tissue immunohistological analysis, and tissue extract-mediated in vitro elastinolysis and collagenolysis assays demonstrated that cystatin C deficiency significantly increased cathepsin expression and activity. In skin from both the chest and ear, we found that the absence of cystatin C reduced epithelial cell apoptosis but increased proliferation. From the same tissue preparations, we detected significantly higher levels of pro-angiogenic laminin 5-derived c2 peptides and concurrently increased neovascularization in cystatin C-deficient mice, compared to those from wild-type control mice. Conclusion: Enhanced cathepsin expression and activity in cystatin C-deficient mice contributed to the progression of dysplasia by altering premalignant tissue epithelial proliferation, apoptosis, and neovascularization.}},
author = {{Yu, Weifang and Liu, Jian and Shi, Michael A. and Wang, Jianan and Xiang, Meixiang and Kitamoto, Shiro and Wang, Bing and Sukhova, Galina K. and Murphy, George F. and Orasanu, Gabriela and Grubb, Anders and Shi, Guo-Ping}},
issn = {{1932-6203}},
language = {{eng}},
number = {{11}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS ONE}},
title = {{Cystatin C Deficiency Promotes Epidermal Dysplasia in K14-HPV16 Transgenic Mice}},
url = {{http://dx.doi.org/10.1371/journal.pone.0013973}},
doi = {{10.1371/journal.pone.0013973}},
volume = {{5}},
year = {{2010}},
}