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Cystatin C Deficiency Promotes Epidermal Dysplasia in K14-HPV16 Transgenic Mice

In English

Författare

  • Weifang Yu
  • Jian Liu
  • Michael A. Shi
  • Jianan Wang
  • Meixiang Xiang
  • Shiro Kitamoto
  • Bing Wang
  • Galina K. Sukhova
  • George F. Murphy
  • Gabriela Orasanu
  • Anders Grubb
  • Guo-Ping Shi
Visa allt

Summary, in English

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.

Publiceringsår

2010

Språk

Engelska

Publikation/Tidskrift/Serie

PLoS ONE

Volym

5

Issue

11

Dokumenttyp

Artikel i tidskrift

Förlag

Public Library of Science (PLoS)

Ämne

  • Medicinal Chemistry
  • Pharmacology and Toxicology

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1932-6203