The role of fibroblast growth factor receptor 2b in skin homeostasis and cancer development
The role of fibroblast growth factor receptor 2b in skin homeostasis and cancer development
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DOI：
10.1038/sj.emboj.7601583
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发表时间：
2007-03-07
期刊：
影响因子：
11.4
通讯作者：
Dickson, Clive
中科院分区：
文献类型：
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作者：
Grose, Richard;Fantl, Vera;Dickson, Clive
成纤维细胞生长因子受体2(FGFR2b)的上皮异构体对于胚胎发育是必不可少的，FGFR2b缺失的小鼠在出生时就会死亡。使用Cre-Lox转基因技术删除表达角蛋白5的细胞中的FGFR2b，我们发现缺乏表皮FGFR2b的小鼠可以存活到成年，但在毛发和皮脂腺发育方面表现出显著的异常。表皮增厚随着年龄的增长而发展，10%的突变小鼠发展为自发性乳头状瘤，证明了FGFR2b在出生后皮肤发育和成人皮肤动态平衡中的作用。缺乏上皮性FGFR2b的小鼠对化学致癌损伤表现出极高的敏感性，表现出几种致癌hras突变，并显著发展为乳头状瘤和鳞状细胞癌。突变小鼠皮肤炎症加剧，巨噬细胞和形态异常的伽马三角洲T细胞数量增加。突变的皮肤表现出几种基因表达的变化，包括促炎细胞因子白介素18的表达增强，以及潜在的肿瘤抑制因子Serpin a3b的表达降低。因此，我们描述了FGFR2b的一个新的作用，并提供了酪氨酸激酶受体在皮肤中发挥肿瘤抑制作用的第一个证据。
The epithelial isoform of fibroblast growth factor receptor 2 (Fgfr2b) is essential for embryogenesis, and Fgfr2b-null mice die at birth. Using Cre-Lox transgenics to delete Fgfr2b in cells expressing keratin 5, we show that mice lacking epidermal Fgfr2b survive into adulthood but display striking abnormalities in hair and sebaceous gland development. Epidermal hyperthickening develops with age, and 10% of mutant mice develop spontaneous papillomas, demonstrating the role of Fgfr2b in post-natal skin development and in adult skin homeostasis. Mice lacking epithelial Fgfr2b show great sensitivity to chemical carcinogenic insult, displaying several oncogenic ha-ras mutations with dramatic development of papillomas and squamous cell carcinomas. Mutant mice have increased inflammation in the skin, with increased numbers of macrophages and gamma delta T cells with abnormal morphology. Mutant skin shows several changes in gene expression, including enhanced expression of the pro-inflammatory cytokine interleukin 18 and decreased expression of Serpin a3b, a potential tumor suppressor. Thus we describe a novel role of Fgfr2b and provide the first evidence of a tyrosine kinase receptor playing a tumor suppressive role in the skin.