Oncogene：FAS信号促进消化道肿瘤上皮间质转化

Fas是一种跨膜蛋白，属于肿瘤坏死因子受体超家族成员，它与FasL结合可以启动凋亡信号的转导引起细胞凋亡。它的活化包括一系列步骤：首先配体诱导受体三聚体化，然后在细胞膜上形成凋亡诱导复合物，这个复合物中包括带有死亡结构域的Fas相关蛋白FADD。

早期研究证实FAS信号参与细胞的凋亡过程。然而，这一信号途径也被证明在促进肿瘤细胞活力，因此产生了FAS信号可诱导上皮间质转化（EMT），以促进肿瘤转移这一假说。

用Fas配体（FasL）处理大肠癌和胃癌细胞以抑制肿瘤细胞中Fas信号，研究人员使用肿瘤运动学方面实验、免疫荧光技术、RT-PCR和免疫印迹分析手段进行了相关实验研究。结果发现FAS信号抑制后下调上皮型细胞标记物，上调间质型细胞标记物，能促进胃肠道（GI）癌细胞的运动。相关研究论文发表在近日Oncogene杂志上。

FasL处理细胞后还增加了EMT细胞核中转录因子的表达，并诱导这些细胞纺锤形细胞形态的形成。敲除Snail或Twist的表达能显著降低FasL蛋白诱导肿瘤细胞运动。 Fas激活ERK1/2通路对FasL蛋白诱导的EMT和肿瘤运动是必须的。

此外，化疗药物奥沙利铂诱导EMT也是部分通过调控Fas信号通路。人消化道癌症患者的临床标本评价结果表明，FasL表达的增加与胃肠癌的发展过程中E-cadherin表达的下降呈负相关性。总之，这些数据表明在体内和体外，FAS信号可能诱发EMT促进肿瘤细胞运动和胃肠癌转移。

doi:10.1016/j.cell.2011.10.017
PMC:
PMID:

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