Fas signaling promotes chemoresistance in gastrointestinal cancer by up-regulating P-glycoprotein.
Fas signaling promotes chemoresistance in gastrointestinal cancer by up-regulating P-glycoprotein.
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Fas信号通过上调P-糖蛋白促进胃肠癌化疗耐药
DOI：
10.18632/oncotarget.2498
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发表时间：
2014-11-15
期刊：
影响因子：
--
通讯作者：
Jiang B
中科院分区：
文献类型：
--
作者：
Zheng H;Liu Z;Liu T;Cai Y;Wang Y;Lin S;Chen J;Wang J;Wang Z;Jiang B
Fas信号通过诱导上皮-间充质转化(EMT)促进胃肠道(GI)癌细胞的转移，而EMT的获得可导致肿瘤的化疗耐药。在这里，我们证明了高表达FasL的胃肠癌患者对化疗的反应明显比低表达的患者差。Fas诱导ERK1/2-MAPK通路的激活降低了GI癌细胞对化疗药物的敏感性，促进了P-糖蛋白(P-gp)的表达。FasL通过上调P-gp，增加β-连环蛋白，降低miR-145，从而促进胃肠道癌细胞的化疗耐药。β-catenin通过与P-gp启动子结合促进P-gp基因转录，而miR145通过与P-gp基因3‘端非编码区相互作用抑制P-gp表达。免疫组织化学染色和定量逆转录聚合酶链式反应分析显示，FasL、β-连环蛋白和P-gp呈正相关，而miR145与FasL和P-gp呈负相关。综上所述，我们的结果表明Fas信号可能通过β-连环蛋白和miR-145调节P-gp的表达来促进GI癌的化疗耐药。我们的发现表明，基于Fas信号的癌症治疗应该谨慎使用，因为激活这一途径不仅可能导致细胞凋亡，还可能导致化疗耐药。
Fas signaling promotes metastasis of gastrointestinal (GI) cancer cells by inducing epithelial-mesenchymal transition (EMT), and EMT acquisition has been found to cause cancer chemoresistance. Here, we demonstrated that the response to chemotherapy of GI cancer patients with higher expression of FasL was significantly worse than patients with lower expression. Fas-induced activation of the ERK1/2-MAPK pathway decreased the sensitivity of GI cancer cells to chemotherapeutic agents and promoted the expression of P-glycoprotein (P-gp). FasL promoted chemoresistance of GI cancer cell via upregulation of P-gp by increasing β-catenin and decreasing miR-145. β-catenin promoted P-gp gene transcription by binding with P-gp promoter while miR-145 suppressed P-gp expression by interacting with the mRNA 3′UTR of P-gp. Immunostaining and qRT-PCR analysis of human GI cancer samples revealed a positive association among FasL, β-catenin, and P-gp, but a negative correlation between miR-145 and FasL or P-gp. Altogether, our results showed Fas signaling could promote chemoresistance in GI cancer through modulation of P-gp expression by β-catenin and miR-145. Our findings suggest that Fas signaling-based cancer therapies should be administered cautiously, as activation of this pathway may not only lead to apoptosis but also induce chemoresistance.
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