Fas signaling induces stemness properties in colorectal cancer by regulation of Bmi1
Fas signaling induces stemness properties in colorectal cancer by regulation of Bmi1
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Fas 信号通过调节 Bmi1 诱导结直肠癌的干性特性
DOI：
10.1002/mc.22680
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发表时间：
2017-10-01
影响因子：
4.6
通讯作者：
Zheng, Haoxuan
中科院分区：
文献类型：
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作者：
Chen, Jiaxuan;Wang, Yadong;Zheng, Haoxuan
Fas信号通过诱导上皮-间质转化（EMT）促进结直肠癌（CRC）转移。EMT特性的获得反过来又诱导了干性，但Fas信号传导对其产生影响的机制仍不清楚。因此，本研究的目的是探讨Fas信号如何调节CRC干性。为此，进行了软琼脂试验、球体形成试验、细胞存活分析、免疫印迹、qRT-PCR、染色质免疫沉淀和荧光素酶报告基因试验。通过免疫组化、qRT-PCR和免疫印迹检测结直肠癌标本中FasL、Bmi 1和miR-200 c的表达。在我们的研究中，Fas信号传导依赖于ERK 1/2 MAPK通路诱导CRC标本中的干细胞特性，其中Bmi 1主要负责FasL诱导的干细胞特性。FasL处理通过抑制靶向Bmi 1 3UTR区域的miR-200 c来促进Bmi 1表达。FasL诱导的Zeb 1与miR-200 c启动子结合并抑制其表达。此外，FasL诱导的catenin核表达通过与Zeb 1启动子结合而促进Zeb 1的表达。GSK-3，调节β-连环蛋白，被FasL诱导的ERK 1/2 MAPK信号转导抑制。最后，FasL和Bmi 1在临床样本中的表达在CRC进展过程中增加，并且观察到它们之间的正相关性。FasL和Bmi 1高表达患者的预后比低表达患者差。总之，我们的研究结果表明，Fas信号可以通过ERK 1/2 MAPK/GSK-3/-catenin/Zeb 1/miR-200 c轴调节Bmi 1表达来促进CRC中的干性，这表明基于Fas信号的癌症治疗应该谨慎施用，因为该途径的激活不仅导致细胞凋亡，而且还诱导CRC中的干性。
Fas signaling promotes colorectal cancer (CRC) metastasis by inducing epithelial-mesenchymal transition (EMT). The acquisition of EMT properties in turn induces stemness but the mechanism by which Fas signaling contributes to it still remains unclear. Hence, the aim of this study was to investigate how Fas signaling regulates CRC stemness. For this purpose, soft agar assay, sphere formation assay, cell survival analysis, immunoblot, qRT-PCR, chromatin immunoprecipitation, and luciferase reporter assay were performed. Expression of FasL, Bmi1, and the miR-200c in CRC specimens was examined through immunohistochemistry, qRT-PCR, and immunoblot. In our study, Fas signaling induced stem cell properties in CRC specimens, relying on ERK1/2 MAPK pathway, with Bmi1 being mainly responsible for FasL-induced stemness. FasL treatment promoted Bmi1 expression by inhibiting miR-200c, which targets Bmi1 3UTR region. Furthermore, FasL-induced Zeb1 binded with miR-200c promoter and inhibited its expression. Moreover, FasL-induced -catenin nuclear expression promoted Zeb1 expression by binding with Zeb1 promoter. GSK-3, which regulates -catenin, was inhibited by FasL-induced ERK1/2 MAPK signaling. Finally, FasL and Bmi1 expression in clinical samples increased during CRC progression, and a positive correlation between them was observed. Patients with high FasL and Bmi1 expression had a worse prognosis than patients with low expression. In conclusion, our results showed that Fas signaling can promote stemness in CRC through the modulation of Bmi1 expression via the ERK1/2 MAPK/GSK-3/-catenin/Zeb1/miR-200c axis, suggesting that Fas signaling-based cancer therapies should be administered cautiously, as the activation of this pathway not only leads to apoptosis but also induces stemness in CRC.