c-KIT-ERK1/2 signaling activated ELK1 and upregulated carcinoembryonic antigen expression to promote colorectal cancer progression.
c-KIT-ERK1/2 signaling activated ELK1 and upregulated carcinoembryonic antigen expression to promote colorectal cancer progression.
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c-KIT-ERK1/2信号激活ELK1并上调癌胚抗原表达促进结直肠癌进展
DOI：
10.1111/cas.14750
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发表时间：
2021-03
期刊：
影响因子：
5.7
通讯作者：
Zhou D
中科院分区：
文献类型：
--
作者：
Ma J;Liu X;Chen H;Abbas MK;Yang L;Sun H;Sun T;Wu B;Yang S;Zhou D
癌胚抗原（CEA）在胚胎和结直肠癌（CRC）中高表达，已被广泛用作CRC的标志物。新出现的证据表明，CEA水平升高促进CRC进展。然而，原发性和复发性CRC患者CEA表达增加的机制仍然是一个悬而未决的问题。在这项研究中，我们发现c-KIT，ELK 1和CEA在CRC患者中高表达，尤其是复发性疾病患者。从生物信息学分析，我们选择ELK 1作为CEA的候选转录因子（TF）; ELK 1在CEA启动子内的结合位点通过染色质免疫沉淀和双荧光素酶报告基因测定来确认。ELK 1的过表达在体外增加了CEA的表达，而ELK 1的敲低降低了CEA。上调的ELK 1促进了CRC细胞的粘附、迁移和侵袭，然而CEA的敲低阻断了ELK 1过表达的CRC细胞的活性。此外，我们探索了c-KIT-ERK 1/2信号转导在ELK 1激活中的作用。使用伊马替尼或ISCK 03阻断c-KIT信号传导降低了CRC细胞中的p-ELK 1表达，从而降低了CEA水平，正如U 0126阻断ERK 1/2途径一样。与野生型同窝小鼠相比，c-kit功能丧失的Wadsm/m小鼠显示c-KIT、ELK 1和CEA表达降低。总之，我们的研究表明，由c-KIT-ERK 1/2信号激活的ELK 1是CEA表达的关键TF。阻断ELK 1或其上游信号可能是减缓CRC进展的另一种方法。除了作为结直肠癌的生物标志物外，癌胚抗原还可用于指导靶向治疗。在c-KIT信号转导激活后，下游ERK 1/2和ELK 1被激活。p-ELK 1可提高CEA转录，从而促进CRC细胞粘附、迁移和侵袭。阻断ELK 1或其上游信号可能是减缓CRC进展的另一种方法。
Carcinoembryonic antigen (CEA) is highly expressed in embryo and colorectal cancer (CRC) and has been widely used as a marker for CRC. Emerging evidence has demonstrated that elevated CEA levels promote CRC progression. However, the mechanism of the increased CEA expression in patients with primary and recurrent CRC is still an open question. In this study, we showed that c‐KIT, ELK1, and CEA were hyperexpressed in patients with CRC, especially patients with recurrent disease. From bioinformatics analysis, we picked ELK1 as a candidate transcription factor (TF) for CEA; the binding site of ELK1 within the CEA promoter was confirmed by chromatin immunoprecipitation and dual luciferase reporter assays. Overexpression of ELK1 increased CEA expression in vitro, while knockdown of ELK1 decreased CEA. Upregulated ELK1 promoted the adhesion, migration, and invasion of CRC cells, however knockdown of CEA blocked the activities of ELK1‐overexpressed CRC cells. Furthermore, we explored the role of c‐KIT‐ERK1/2 signaling in activation of ELK1. Blocking c‐KIT signaling using Imatinib or ISCK03 reduced p‐ELK1 expression and consequently decreased CEA levels in CRC cells, as did blocking the ERK1/2 pathway by U0126. Compared with wild type littermates, the c‐kit loss‐of‐functional Wadsm/m mice showed lowered c‐KIT, ELK1, and CEA expression. In conclusion, our study revealed that ELK1, which was activated by c‐KIT‐ERK1/2 signaling, was a key TF for CEA expression. Blocking ELK1 or its upstream signaling could be an alternative way to decelerate CRC progression. Besides being a biomarker for CRC, CEA could be used for guiding targeted therapy. Upon activation of c‐KIT signaling, downstream ERK1/2 and ELK1 are activated. p‐ELK1 elevates CEA transcription, which promotes CRC cell adhesion, migration, and invasion. Blocking ELK1 or its upstream signaling could be an alternative way to decelerate CRC progression.
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影响因子：
7.3
作者：
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影响因子：
64.5
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通讯作者：
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影响因子：
10.9
作者：
Gonzalez-Exposito, Reyes;Semiannikova, Maria;Gerlinger, Marco
通讯作者：
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