為了驗(yàn)證表皮發(fā)育是否與Smad信號(hào)途徑有關(guān),，Oregon  Health  &  Science大學(xué)研究人員韓港文（Gangwen  Han,，音譯）等利用基因工程手段得到角化細(xì)胞（包括皮膚干細(xì)胞）能夠分泌Smad7的實(shí)驗(yàn)小鼠。Smad7對(duì)Smad有拮抗作用,。結(jié)果顯示,，毛囊（hair  follicle）形態(tài)發(fā)生和分化不穩(wěn)定，但是皮脂腺（sebaceous  gland）形態(tài)發(fā)生得到增強(qiáng),。

        進(jìn)一步研究發(fā)現(xiàn),，Smad7不僅具有抑制Smad信號(hào)途徑的作用，而且能夠綁定β-catenin,，通過(guò)向Smad7－β-catenin復(fù)合體周圍募集E3連接酶Smurf2,，誘導(dǎo)β-catenin降解,。結(jié)果，在經(jīng)過(guò)Smad7基因改造的毛囊中,，Wnt/β-catenin信號(hào)途徑受到抑制,。共表達(dá)Smurf2和Smad7會(huì)使Smad7誘導(dǎo)的毛囊和皮脂腺畸形事件加劇,；相反,，敲除內(nèi)源性Smad7基因，角化細(xì)胞中β-catenin蛋白的表達(dá)量上升,，Wnt的信號(hào)途徑加強(qiáng),。

        這些結(jié)果揭示了Smad7基因拮抗Wnt/β-catenin信號(hào)途徑的機(jī)制，影響從毛囊形成到皮脂腺形成的一系列表皮細(xì)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.

更多原文鏈接：http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1142114