L1CAM drives oncogenicity in esophageal squamous cell carcinoma by stimulation of ezrin transcription
L1CAM drives oncogenicity in esophageal squamous cell carcinoma by stimulation of ezrin transcription
复制标题
L1CAM 通过刺激 ezrin 转录驱动食管鳞状细胞癌的致癌性
DOI：
10.1007/s00109-017-1595-4
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发表时间：
2017-12-01
影响因子：
4.7
通讯作者：
Xie, Jian-Jun
中科院分区：
文献类型：
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作者：
Guo, Jin-Cheng;Xie, Yang-Min;Xie, Jian-Jun
L1细胞粘附分子（L1 CAM）在人类多种肿瘤中高度表达，其致癌机制尚不清楚。在这里，我们发现，L1 CAM的表达显着增加，食管鳞状细胞癌（ESCC;n= 157）病变相比，非癌组织。高肿瘤L1 CAM表达与总生存率降低显著相关。在实验中，L1 CAM敲低导致细胞生长、迁移和体外侵袭力降低，而L1 CAM过表达则表现出相反的效果。在裸鼠中，L1 CAM耗竭减弱了肿瘤发生和穿透ESCC细胞周围组织的能力。基因集富集分析（GSEA）和SubpathwayMiner基因表达谱分析（ESCC组织的微阵列数据，GSE 53625; L1 CAM-敲低ESCC细胞系的cDNA微阵列数据，GSE 86268）表明，L1 CAM-共表达基因与细胞运动、细胞增殖和肌动蛋白细胞骨架的调节相关，验证了上述实验结果。进一步的机制分析表明，L1 CAM通过激活整合素β1/MAPK/ERK/AP 1信号通路上调细胞骨架蛋白ezrin的表达，导致ESCC细胞恶性表型的发生。在一起，我们的研究结果表明，L1 CAM可作为食管鳞癌患者有价值的预后标志物和治疗靶点，L1 CAM通过上调Ezrin表达促进食管鳞癌的致瘤性。关键信息L1 CAM促进食管鳞癌细胞的生长和侵袭力。L1 CAM通过整合素α5β1/MAPK/ERK/AP 1途径上调Ezrin的表达。Ezrin是L1 CAM中的一个关键下游效应子，在ESCC中起重要作用。L1 CAM和ezrin的高表达水平与总生存率降低显著相关，核L1 CAM是食管鳞癌独立的预后指标。
AbstractL1 cell adhesion molecule (L1CAM) is highly expressed in various types of human cancers, displaying yet unknown molecular mechanisms underlying their oncogenic potential. Here, we found that L1CAM expression was significantly increased in esophageal squamous cell carcinoma (ESCC;n= 157) lesions compared with non-cancerous tissues. High tumorous L1CAM expression significantly correlated with reduced overall survival. Experimentally, L1CAM knockdown led to decreased cell growth, migration, and invasiveness in vitro, whereas overexpression of L1CAM showed the opposite effect. In nude mice, L1CAM depletion attenuated tumorigenesis and ability to penetrate the tissues surrounding ESCC cells. Gene set enrichment analysis (GSEA) and SubpathwayMiner analysis on gene expression profiles (microarray data on ESCC tissues, GSE53625; cDNA microarray data on L1CAM-knockdown ESCC cell line, GSE86268) suggested that L1CAM-co-expression genes were related to cell motility, cell proliferation, and regulation of actin cytoskeleton, validating the above experimental findings. Further mechanistical analysis showed that L1CAM upregulated the expression of the cytoskeletal protein ezrin via activating integrin β1/MAPK/ERK/AP1 signaling and thus led to the malignant phenotypes of ESCC cells. Together, our findings suggest that L1CAM may be employed as a valuable prognosis marker and a therapeutic target for ESCC patients and that L1CAM promotes ESCC tumorigenicity by upregulating ezrin expression.Key messagesL1CAM promotes growth and invasiveness of ESCC cells in vitro and in vivo.L1CAM upregulates the expression of ezrin by integrin α5β1/MAPK/ERK/AP1 pathway.Ezrin is a key downstream effector in the L1CAM-promoted malignant phenotypes.High expression levels of both L1CAM and ezrin significantly correlated with reduced overall survival.Nuclear L1CAM is an independent prognosis marker for esophageal squamous cell carcinoma.