Cystatin C deficiency promotes epidermal dysplasia in K14-HPV16 transgenic mice.
Cystatin C deficiency promotes epidermal dysplasia in K14-HPV16 transgenic mice.
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DOI：
10.1371/journal.pone.0013973
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发表时间：
2010-11-15
期刊：
影响因子：
3.7
通讯作者：
Shi GP
中科院分区：
文献类型：
--
作者：
Yu W;Liu J;Shi MA;Wang J;Xiang M;Kitamoto S;Wang B;Sukhova GK;Murphy GF;Orasanu G;Grubb A;Shi GP
半胱氨酸蛋白酶组织蛋白酶在细胞外基质蛋白降解、细胞凋亡和血管生成中是重要的。在几种动物模型中，缺乏组织蛋白酶的小鼠被保护免于肿瘤进展，这表明组织蛋白酶活性的调节控制各种恶性肿瘤的生长。我们使用多阶段上皮癌变的小鼠模型测试了组织蛋白酶的作用，其中人角蛋白-14启动子/增强子驱动人乳头瘤病毒16型（HPV 16）早期区域E6/E7转基因的表达。在癌前发育不良的进展过程中，我们观察到半胱氨酸蛋白酶组织蛋白酶S的表达增加，但同时减少了皮肤组织提取物中组织蛋白酶内源性抑制剂胱抑素C的表达。在这些转基因小鼠中缺乏半胱氨酸蛋白酶抑制剂C导致面部、耳部、胸部和尾部的异型增生进一步发展为原位癌。胸部和耳部皮肤提取物真实的时间PCR和免疫印迹分析，小鼠血清样品ELISA，组织免疫组织学分析，和组织提取物介导的体外弹性蛋白溶解和胶原溶解试验表明，胱抑素C缺乏显着增加组织蛋白酶的表达和活性。在胸部和耳部的皮肤中，我们发现半胱氨酸蛋白酶抑制剂C的缺乏减少了上皮细胞的凋亡，但增加了增殖。从相同的组织制备物中，我们检测到与野生型对照小鼠相比，半胱氨酸蛋白酶抑制剂C缺陷小鼠中促血管生成层粘连蛋白5衍生的γ2肽的水平显著更高，同时新血管形成增加。在胱抑素C缺陷小鼠中，组织蛋白酶表达和活性增强通过改变癌前组织上皮细胞增殖、细胞凋亡和新生血管形成促进异型增生的进展。
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.
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