CHEMICAL SKIN CARCINOGENESIS IS PREVENTED IN MICE BY THE INDUCED EXPRESSION OF A TGF-BETA RELATED TRANSGENE
CHEMICAL SKIN CARCINOGENESIS IS PREVENTED IN MICE BY THE INDUCED EXPRESSION OF A TGF-BETA RELATED TRANSGENE
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DOI：
10.1002/tcm.1770150103
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发表时间：
1995-01-01
期刊：
影响因子：
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通讯作者：
HOGAN, BLM
中科院分区：
文献类型：
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作者：
BLESSING, M;NANNEY, LB;HOGAN, BLM
皮肤乳头状瘤和鳞状细胞癌(SCCs)是由致癌物质诱发，然后用佛波酯12-O-十四烷基佛波醇-13-醋酸酯(TPA)促癌。这些通常发生于癌前病变，以表皮增殖和增殖、真皮水肿和炎症为特征。为了评估多肽生长因子在化学诱导的皮肤癌变中的作用，我们使用了携带转化生长因子-β相关分子骨形态发生蛋白-4(BMP-4)的转基因小鼠，在皮肤癌发生方案中细胞角蛋白IV*基因的调控元件的控制下。对照非转基因小鼠和BMP-4转基因小鼠接受单剂量致癌剂N-甲基-N‘-亚硝基胍(MNNG)治疗，并与肿瘤促进剂TPA进行为期9个月的两周治疗。在对照仔鼠中，TPA诱导了表皮过度增殖、暗细胞异型性和真皮炎症，导致了26只受试动物中的13只出现乳头状瘤和鳞状细胞。在BMP-4转基因小鼠中，TPA治疗诱导了BMP-4转基因在毛囊间表皮中的表达，但在初始剂量TPA后仅观察到轻微的表皮增厚、过度增殖和炎症。此外，TPA处理9个月后，转基因表皮的有丝分裂指数显著低于未处理的转基因表皮。因此，测试的22只转基因动物中没有一只患上乳头状瘤或鳞状细胞癌。综上所述，我们发现TPA诱导的BMP-4转基因表达阻止了皮肤的增殖和炎症，这是随后乳头状瘤和鳞状细胞形成的关键步骤，我们还鉴定了一个可诱导的启动子系统，在外源刺激后毛囊间表皮表达多肽。(C)1995年Wiley-Liss公司
Skin papillomas and squamous cell carcinomas (SCCs) are induced in mice by tumor initiation with a carcinogen followed by tumor promotion with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). These usually arise from preneoplastic lesions characterized by epidermal proliferation and hyperplasia, dermal edema, and inflammation. To evaluate the role of polypeptide growth factors in chemically induced skin carcinogenesis, we used transgenic mice carrying the cDNA for a TGF-beta related molecule, bone morphogenetic protein-4 (BMP-4), under the control of the regulatory elements of the cytokeratin IV* gene in a skin carcinogenesis protocol.Control non-transgenic littermates and BMP-4 transgenic mice were treated with a single dose of a carcinogen, N-methyl-N'-nitrosoguanidine (MNNG), and biweekly with the tumor promoter TPA for 9 months. In control littermates TPA induced epidermal hyperproliferation, atypia with ''dark'' cells, and dermal inflammation, resulting in papillomas and SCCs in 13 of 26 animals tested. In BMP-4 transgenic mice, TPA treatment induced the expression of the BMP-4 transgene in interfollicular epidermis but only minimal epidermal thickening, hyperproliferation, and inflammation were noted after the initial dose of TPA. Furthermore, the mitotic indices in transgenic epidermis after 9 months of TPA treatment were significantly lower than the corresponding indices from untreated transgenic epidermis. Consequently, none of the 22 transgenic animals tested developed papillomas or SCCs. In conclusion, we have shown that the TPA induced expression of the BMP-4 transgene blocks proliferation and inflammation in skin, steps that are critical to the subsequent formation of papillomas and SCCs and we characterized an inducible promotersystem which expresses polypeptides in interfollicular epidermis after exogenous stimulation. (C) 1995 Wiley-Liss, Inc.