Tumor endothelial cells promote metastasis and cancer stem cell-like phenotype through elevated Epiregulin in esophageal cancer.
Tumor endothelial cells promote metastasis and cancer stem cell-like phenotype through elevated Epiregulin in esophageal cancer.
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发表时间：
2016-10
影响因子：
5.3
通讯作者：
Li-chao Sun;Jian Pan;Long Yu;Huiqi Liu;X. Shu;Li-xin Sun;J. Lou;Zhihua Yang;Y. Ran
中科院分区：
文献类型：
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作者：
Li-chao Sun;Jian Pan;Long Yu;Huiqi Liu;X. Shu;Li-xin Sun;J. Lou;Zhihua Yang;Y. Ran
已经发现肿瘤内皮细胞与转移和癌症进展相关。在这项研究中，我们报告了人食管癌内皮细胞（HECEC），不同于相应的人食管正常内皮细胞（HENEC），显示了一些独特的特征与独特的基因表达谱。进一步的研究表明，HECEC可以通过直接的细胞-细胞相互作用增强食管癌细胞的迁移、侵袭和自我更新能力。体内实验表明HECEC能显著增强食管癌细胞的侵袭和肺转移能力。为了阐明HECEC在食管癌发生发展中的分子机制，我们采用基因芯片技术分析了HECEC、HENEC和HECEC条件培养基治疗前后基因表达谱的变化。在高表达的HECEC调控基因中，我们重点关注了上皮调节蛋白（EREG）。进一步的研究表明，EREG在EC 9706或Kyse 30细胞中的过表达可以诱导肌动蛋白重组、球体形成能力和CD 44+肿瘤干细胞样细胞的显著富集。食管癌细胞EREG表达上调可增加食管癌细胞的肺转移，缩短食管癌细胞的生存期。进一步研究表明EREG可诱导Src和FAK的活化。此外，所有这些作用也可以被功能阻断性抗EREG抗体以剂量依赖性方式抑制。免疫组化分析显示EREG高表达与淋巴结转移和预后不良密切相关。综上所述，HECEC通过Epiregulin在增强食管癌细胞的侵袭、迁移、肿瘤干细胞表型和转移潜能方面发挥关键作用。
Tumor endothelial cells have been found to be associated with metastasis and cancer progression. In this study, we reported that human esophageal cancer endothelial cells (HECEC), unlike corresponding human esophageal normal endothelial cells (HENEC) displayed several distinct feature couple with unique gene expression profile. Further studies showed that HECEC can enhance migration, invasion and self-renewal properties of esophageal carcinoma cell in vitro by a direct cell-cell interaction. In vivo assay demonstrated that HECEC could significantly enhance the invasion and lung metastasis of esophageal cancer cells. To elucidate the molecular mechanisms of HECEC in esophageal carcinoma progression, we employed the microarray to analyze the gene expression profiles before and after treating with HECEC, HENEC or conditioned meium from HECEC. Among the highly expressed HECEC-regulated genes, we focused on Epiregulin (EREG). Further studies demonstrated that overexpression of EREG in EC9706 or Kyse30 cells can induce actin reorganization, sphere formation ability and a significantly enrichment of CD44+ cancer stem-like cells. Moreover, up-regulation of EREG in esophageal cancer cells could enhance lung metastasis and decrease the survival time in vivo. Further study indicated that EREG could induce activation of the Src and FAK. In addition, all these effects could also be inhibited by the function-blocking anti-EREG antibody in a dose dependent manner. Immunohistochemical analysis revealed that high level of EREG was significantly correlated with lymph node metastases and poor prognosis. In summary, HECEC play key roles in enhancing the invasion, migration, cancer stem cell phenotype and metastatic potential of esophageal cancer cells through Epiregulin.