Cystatin C deficiency promotes epidermal dysplasia in K14-HPV16 transgenic mice

• Published in: PloS one 2010-11, Vol.5 (11), p.e13973
• Main Authors: 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, Shi, Guo-Ping
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Animal models; Animals; Apoptosis; Ataxia; Basic Medicine; Biodegradation; Brain cancer; Carcinogenesis; Carcinogens; Carcinoma; Cardiology; Cathepsin S; Cathepsins; Cathepsins - genetics; Cathepsins - metabolism; Cell Biology/Extra-Cellular Matrix; Cell Proliferation; Chest; Collagen; Cystatin; Cystatin C; Cystatin C - deficiency; Cystatin C - genetics; Cystatin C - metabolism; Cysteine; Cysteine proteinase; Disease Progression; Dysplasia; Ear; Early region; Elastin; Enzyme-linked immunosorbent assay; Epidermis - metabolism; Epidermis - pathology; Epithelial cells; Extracellular matrix; Farmakologi och toxikologi; Female; Genes; Genetic engineering; Human papillomavirus; Human papillomavirus 16; Human papillomavirus 16 - genetics; Humans; Hyperplasia; Immunoblotting; Keratin; Keratin-14 - genetics; Laminin; Läkemedelskemi; Male; Matrix protein; Medical and Health Sciences; Medical schools; Medicin och hälsovetenskap; Medicinal Chemistry; Medicine; Medicinska och farmaceutiska grundvetenskaper; Melanoma; Metastasis; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neovascularization; Oncogene Proteins, Viral - genetics; Oncology/Skin Cancers; Papillomavirus E7 Proteins - genetics; Papillomavirus infections; Pathology/Pathophysiology; Pathology/Surgical Pathology; Peptides; Pharmacology and Toxicology; Polymerase chain reaction; Promoter Regions, Genetic - genetics; Promoters; Prostate; Protease; Proteolysis; Repressor Proteins - genetics; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Skin; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Tails; Tissue analysis; Tissues; Transgenes; Transgenic mice; Tumorigenesis; Tumors; vascularization; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0013973

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. 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 γ2 peptides and concurrently increased neovascularization in cystatin C-deficient mice, compared to those from wild-type control mice. 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.