为了验证表皮发育是否与Smad信号途径有关,Oregon Health & Science大学研究人员韩港文(Gangwen Han,音译)等利用基因工程手段得到角化细胞(包括皮肤干细胞)能够分泌Smad7的实验小鼠。Smad7对Smad有拮抗作用。结果显示,毛囊(hair follicle)形态发生和分化不稳定,但是皮脂腺(sebaceous gland)形态发生得到增强。
进一步研究发现,Smad7不仅具有抑制Smad信号途径的作用,而且能够绑定β-catenin,通过向Smad7-β-catenin复合体周围募集E3连接酶Smurf2,诱导β-catenin降解。结果,在经过Smad7基因改造的毛囊中,Wnt/β-catenin信号途径受到抑制。共表达Smurf2和Smad7会使Smad7诱导的毛囊和皮脂腺畸形事件加剧;相反,敲除内源性Smad7基因,角化细胞中β-catenin蛋白的表达量上升,Wnt的信号途径加强。
这些结果揭示了Smad7基因拮抗Wnt/β-catenin信号途径的机制,影响从毛囊形成到皮脂腺形成的一系列表皮细胞分化程序。
部分英文原文:
Distinct mechanisms of TGF-β1–mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis
In the present study, we demonstrated that human skin cancers frequently overexpress TGF-β1 but exhibit decreased expression of the TGF-β type II receptor (TGF-βRII). To understand how this combination affects cancer prognosis, we generated a transgenic mouse model that allowed inducible expression of TGF-β1 in keratinocytes expressing a dominant negative TGF-βRII (βRII) in the epidermis. Without βRII expression, TGF-β1 transgene induction in late-stage, chemically induced papillomas failed to inhibit tumor growth but increased metastasis and epithelial-to-mesenchymal transition (EMT), i.e., formation of spindle cell carcinomas. Interestingly, βRII expression abrogated TGF-β1–mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-β1/βRII compound tumors. Furthermore, expression of molecules thought to mediate TGF-β1–induced EMT was attenuated in TGF-β1/βRII–transgenic tumors. However, TGF-β1/βRII–transgenic tumors progressed to metastasis without losing expression of the membrane-associated E-cadherin/catenin complex and at a rate higher than those observed in nontransgenic, TGF-β1–transgenic, or βRII-transgenic mice. Abrogation of Smad activation by βRII correlated with the blockade of EMT. However, βRII did not alter TGF-β1–mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-β1 induces EMT and invasion via distinct mechanisms. TGF-β1–mediated EMT requires functional TGF-βRII, whereas TGF-β1–mediated tumor invasion cooperates with reduced TGF-βRII signaling in tumor epithelia.
更多原文链接:http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1142114