Fas是一種跨膜蛋白,，屬于腫瘤壞死因子受體超家族成員，它與FasL結(jié)合可以啟動凋亡信號的轉(zhuǎn)導(dǎo)引起細(xì)胞凋亡,。它的活化包括一系列步驟：首先配體誘導(dǎo)受體三聚體化,，然后在細(xì)胞膜上形成凋亡誘導(dǎo)復(fù)合物，這個復(fù)合物中包括帶有死亡結(jié)構(gòu)域的Fas相關(guān)蛋白FADD,。
早期研究證實FAS信號參與細(xì)胞的凋亡過程,。然而，這一信號途徑也被證明在促進(jìn)腫瘤細(xì)胞活力,，因此產(chǎn)生了FAS信號可誘導(dǎo)上皮間質(zhì)轉(zhuǎn)化（EMT）,，以促進(jìn)腫瘤轉(zhuǎn)移這一假說。
用Fas配體（FasL）處理大腸癌和胃癌細(xì)胞以抑制腫瘤細(xì)胞中Fas信號,，研究人員使用腫瘤運動學(xué)方面實驗,、免疫熒光技術(shù)、RT-PCR和免疫印跡分析手段進(jìn)行了相關(guān)實驗研究,。結(jié)果發(fā)現(xiàn)FAS信號抑制后下調(diào)上皮型細(xì)胞標(biāo)記物,，上調(diào)間質(zhì)型細(xì)胞標(biāo)記物，能促進(jìn)胃腸道（GI）癌細(xì)胞的運動,。相關(guān)研究論文發(fā)表在近日Oncogene雜志上,。
FasL處理細(xì)胞后還增加了EMT細(xì)胞核中轉(zhuǎn)錄因子的表達(dá)，并誘導(dǎo)這些細(xì)胞紡錘形細(xì)胞形態(tài)的形成,。敲除Snail或Twist的表達(dá)能顯著降低FasL蛋白誘導(dǎo)腫瘤細(xì)胞運動,。 Fas激活ERK1/2通路對FasL蛋白誘導(dǎo)的EMT和腫瘤運動是必須的。
此外,，化療藥物奧沙利鉑誘導(dǎo)EMT也是部分通過調(diào)控Fas信號通路,。人消化道癌癥患者的臨床標(biāo)本評價結(jié)果表明，F(xiàn)asL表達(dá)的增加與胃腸癌的發(fā)展過程中E-cadherin表達(dá)的下降呈負(fù)相關(guān)性,?？傊@些數(shù)據(jù)表明在體內(nèi)和體外,，F(xiàn)AS信號可能誘發(fā)EMT促進(jìn)腫瘤細(xì)胞運動和胃腸癌轉(zhuǎn)移,。（生物谷：Bioon.com）
doi:10.1016/j.cell.2011.10.017
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Fas signaling promotes motility and metastasis through epithelial-mesenchymal transition in gastrointestinal cancer.
Zheng HX, Cai YD, Wang YD, Cui XB, Xie TT, Li WJ, Peng L, Zhang Y, Wang ZQ, Wang J, Jiang B.
Fas signaling was reported to participate in cell apoptosis. However, this pathway has also been shown to promote tumor cell motility, leading to the hypothesis that Fas signaling may induce epithelial-mesenchymal transition (EMT) to promote metastasis. The effects of Fas-ligand (FasL) treatment and inhibition of Fas signaling on colorectal and gastric cancer cells were tested using motility assay, immunofluorescence, RT-PCR and immunoblot analyses. Fas signaling downregulated epithelial markers, upregulated mesenchymal markers and promoted motility in gastrointestinal (GI) cancer cells. FasL treatment also increased the expression of EMT transcriptional factors in the nucleus and induced a spindle shape cell morphology in these cells. Knockdown of Snail or Twist expression significantly decreased FasL-induced motility. The ERK1/2 pathway was activated by Fas signaling and is required for FasL-induced EMT and motility. Moreover, oxaliplatin, a chemotherapeutic agent, induced EMT partly through Fas signaling. Evaluation of human GI clinical specimens showed that FasL expression increased whereas E-cadherin expression decreased during GI cancer progression. Both markers were significantly inversely correlated. Tissue samples with a non-EMT phenotype were mainly distributed in patients with early cancer stages, whereas samples with an EMT phenotype were mostly distributed in patients with advanced cancer stages. A non-EMT phenotype significantly correlated with better prognosis. Altogether, these data indicate that Fas signaling may induce EMT to promote tumor motility and metastasis in GI cancer in vivo and in vitro
