Ghali L, Wong S T, Green J, Tidman N, Quinn A G
Center for Cutaneous Research, St Batholomew's & The Royal London Hospital School of Medicine & Dentistry, Whitechapel, UK.
J Invest Dermatol. 1999 Oct;113(4):595-9. doi: 10.1046/j.1523-1747.1999.00729.x.
Genetic studies of patients with the nevoid basal cell carcinoma syndrome have led to the recognition of the importance of the hedgehog signaling pathway in the development of basal cell carcinomas of the skin. Although hedgehog signaling is known to be important in hair follicle development, the function of this pathway in adult skin and the mechanism by which activation of this pathway leads to basal cell carcinoma development remain to be established. The Gli1 family of transcription factors mediates hedgehog signaling in mammalian cells and we have shown in previous studies that Gli1 mRNA is differentially expressed in basal cell carcinomas. Using antibodies to epitopes on the N and C terminal regions of Gli1 we show now that Gli1 protein is present in basal cell carcinomas and that the protein is mainly localized to the cytoplasmic compartment. Focal nuclear staining was seen in a small number of basal cell carcinomas with the C terminal antibody which suggest that nuclear localization is not dependent on loss of the C terminus of Gli1 due to proteolysis. Strong Gli1 immunostaining was seen in the outer root sheath keratinocytes of some hair follicles, a subpopulation of mesenchymal cells in the vicinity of the bulge region of adult hair follicles and the dermal sheath cells of developing hair follicles. Quantitation of Gli1 mRNA in basal cell carcinomas using northern blot analysis indicates that Gli1 is highly expressed in basal cell carcinomas. This suggests that the lower intensity of Gli1 immunostaining in basal cell carcinoma islands relative to outer root sheath keratinocytes is not simply a reflection of differences in gene expression. The continued expression of Gli1 in adult hair follicles and in the mesenchyme of adult human skin suggest that Hh signaling may play a part in hair cycling and in epidermal mesenchymal interactions important in normal skin maintenance.
对痣样基底细胞癌综合征患者的基因研究，已使人们认识到刺猬信号通路在皮肤基底细胞癌发生发展中的重要性。尽管已知刺猬信号通路在毛囊发育中很重要，但该通路在成人皮肤中的功能以及该通路激活导致基底细胞癌发生的机制仍有待确定。Gli1转录因子家族在哺乳动物细胞中介导刺猬信号通路，我们在先前的研究中已表明Gli1 mRNA在基底细胞癌中差异表达。现在，我们使用针对Gli1 N端和C端区域表位的抗体，发现Gli1蛋白存在于基底细胞癌中，且该蛋白主要定位于细胞质区室。用C端抗体在少数基底细胞癌中可见局灶性核染色，这表明核定位并不依赖于因蛋白水解导致的Gli1 C端缺失。在一些毛囊的外根鞘角质形成细胞、成人毛囊隆突区附近的间充质细胞亚群以及发育中毛囊的真皮鞘细胞中可见强Gli1免疫染色。使用Northern印迹分析对基底细胞癌中的Gli1 mRNA进行定量，结果表明Gli1在基底细胞癌中高表达。这表明相对于外根鞘角质形成细胞，基底细胞癌岛中Gli1免疫染色强度较低并非仅仅是基因表达差异的反映。Gli1在成人毛囊和成人皮肤间充质中的持续表达表明，Hh信号通路可能在毛发周期以及正常皮肤维持中重要的表皮-间充质相互作用中发挥作用。
