Dual role for Id2 in chemical carcinogen-induced skin tumorigenesis
Dual role for Id2 in chemical carcinogen-induced skin tumorigenesis
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Id2 在化学致癌物诱导的皮肤肿瘤发生中的双重作用
作者：
Tokuriki;A.;Iyoda;T.;Inaba;K.;Ikuta;K.;Fujimoto;S.;Kumakiri;M. and Yokota;Y
DNA结合抑制因子2(Id2)是碱性螺旋-环-螺旋转录因子的负调控因子，参与细胞分化和增殖的调控。通过使用两步化学致癌方案，我们评估了Id2在小鼠皮肤肿瘤形成中的作用。接种20周后，Id2−/−小鼠的肿瘤形成率是野生型的3.5倍，而Id2−/−小鼠的肿瘤直径约为野生型的一半。在Id2−/−小鼠中，几乎检测不到在皮肤肿瘤发展的免疫监控中发挥关键作用的表皮γδT细胞。虽然组织学分析显示Id2−/−小鼠在肿瘤细胞类型、肿瘤血管形成和细胞凋亡方面没有明显差异，但与野生型小鼠相比，Id2小鼠肿瘤中增殖细胞的比例减少。在野生型小鼠中，Id2在皮肤肿瘤中的表达高于在耳上皮细胞中的表达。生化分析显示Id2−/−小鼠肿瘤细胞周期蛋白D1在蛋白水平上降低，而其他因子如细胞周期蛋白E和p27无明显变化。我们的结果表明，Id2在皮肤肿瘤的发生中起着双重作用，它通过建立表皮γδT细胞介导的皮肤免疫监视机制抑制肿瘤的发展，并通过控制细胞周期蛋白D1水平促进肿瘤细胞的增殖。
Inhibitor of DNA binding 2 (Id2) is a negative regulator of basic helix-loop-helix transcription factors and is involved in the control of cellular differentiation and proliferation. By using a two-step chemical carcinogenesis protocol, we evaluated the role of Id2 in skin tumor formation in mice. Twenty weeks after the initiation, the number of tumors formed in theId2−/−mice was 3.5-fold higher than that in their wild-type littermates, whereas the diameter of tumors in theId2−/−mice was about half of that of the tumors in the wild-type mice. In theId2−/−mice, epidermal γδ T cells, which play a key role in immunosurveillance against skin tumor development, were barely detectable. Although histological analyses demonstrated no apparent difference in tumor cell type, tumor vessel formation or apoptosis, the proportion of proliferating cells was reduced in the tumors in theId2−/−mice compared with those in the wild-type mice. In the wild-type mice, the expression ofId2was enhanced in skin tumors compared with that in ear epidermal cells. Biochemical analysis demonstrated that cyclin D1 was reduced at the protein level in the tumors in theId2−/−mice, whereas other factors such as cyclin E and p27 were not altered significantly. Our results reveal that Id2 plays a dual role in skin tumorigenesis by suppressing tumor development through the establishment of epidermal γδ T cell-mediated skin immunosurveillance and by promoting tumor cell proliferation via the control of the cyclin D1 protein level.