Abstract
BackgroundCysteine 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 ResultsWe 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.ConclusionEnhanced cathepsin expression and activity in cystatin C-deficient mice contributed to the progression of dysplasia by altering premalignant tissue epithelial proliferation, apoptosis, and neovascularization.
Highlights
Cysteine protease cathepsins are secretory lysosomal proteases that mediate both intracellular and extracellular protein degradation
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
We introduced cystatin C mutant alleles into the invasive epidermis multistage squamous-cell carcinoma (SCC) mouse model [27], in which the human keratin-14 promoter/ enhancer drove the expression of human papillomavirus human papillomavirus type 16 (HPV16) early region genes, including the E6/E7 oncogenes, to test whether absence of this dominant cathepsin inhibitor alters the progression of premalignant dysplasia
Summary
Cysteine protease cathepsins are secretory lysosomal proteases that mediate both intracellular and extracellular protein degradation. RNAi-mediated CatB inhibition reduced meningioma cell migration and invasion and led to significant regression of pre-established orthotopic tumors [9]. Similar observations were made in a RIP-Tag transgenic mouse pancreatic islet cell carcinoma model, in which the rat insulin II promoter (RIP) drove expression of the SV40 large T-antigen (Tag). These tumors had increased cathepsin expression, which associated with angiogenic vasculature along the invasive front. Reduction in the activity of cathepsins using the pharmacologic inhibitor JPM, or deficiency of CatS, impaired angiogenic switch in progenitor lesions, affecting angiogenesis, tumor growth, vascularity, and invasiveness [12,13]. 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
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