文章：

EBP50缺失与核β-连环蛋白积聚通过诱导肿瘤出芽促进结直肠癌侵袭行为

EBP50 Depletion and Nuclear β-Catenin Accumulation Engender Aggressive Behavior of Colorectal Carcinoma through Induction of Tumor Budding

原文发布日期：29 December 2023

DOI: 10.3390/cancers16010183

类型: Article

开放获取: 是

英文摘要：

Ezin-radixin-moesin-binding phosphoprotein 50 (EBP50) is a scaffold protein that interacts with several partner molecules including β-catenin. Here, we examined the crosstalk between EBP50 and nuclear catenin during colorectal carcinoma (CRC) progression. In clinical samples, there were no correlations between the subcellular location of EBP50 and any clinicopathological factors. However, EBP50 expression was significantly lower specifically in the outer areas of tumor lesions, in regions where tumor budding (BD) was observed. Low EBP50 expression was also significantly associated with several unfavorable prognostic factors, suggesting that EBP50 depletion rather than its overexpression or subcellular distribution plays an important role in CRC progression. In CRC cell lines, knockout of EBP50 induced epithelial–mesenchymal transition (EMT)-like features, decreased proliferation, accelerated migration capability, and stabilized nuclear β-catenin due to disruption of the interaction between EBP50 and β-catenin at the plasma membrane. In addition, Slug expression was significantly higher in outer lesions, particularly in BD areas, and was positively correlated with nuclear β-catenin status, consistent with β-catenin-driven transactivation of the Slug promoter. Together, our data suggest that EBP50 depletion releases β-catenin from the plasma membrane in outer tumor lesions, allowing β-catenin to accumulate and translocate to the nucleus, where it transactivates the Slug gene to promote EMT. This in turn triggers tumor budding and contributes to the progression of CRC to a more aggressive phase.

摘要翻译： 

Ezin-radixin-moesin结合磷蛋白50（EBP50）是一种支架蛋白，可与包括β-连环蛋白在内的多种伴侣分子相互作用。本研究探讨了结直肠癌（CRC）进展过程中EBP50与核内连环蛋白之间的交互作用。临床样本分析显示，EBP50的亚细胞定位与任何临床病理因素均无相关性。然而，在肿瘤病灶的外周区域，特别是在观察到肿瘤出芽（BD）的区域，EBP50表达显著降低。低EBP50表达还与多种不良预后因素显著相关，表明EBP50的缺失（而非其过表达或亚细胞分布）在CRC进展中起重要作用。在CRC细胞系中，敲除EBP50可诱导上皮-间质转化（EMT）样特征，降低增殖能力，加速迁移能力，并因质膜上EBP50与β-连环蛋白相互作用被破坏而稳定核内β-连环蛋白。此外，Slug表达在肿瘤外周病灶（尤其是BD区域）显著升高，且与核内β-连环蛋白状态呈正相关，这与β-连环蛋白驱动Slug启动子反式激活的机制一致。综上，我们的数据表明：在肿瘤外周病灶中，EBP50缺失使β-连环蛋白从质膜释放，进而积累并转位至细胞核，通过反式激活Slug基因促进EMT。这一过程最终触发肿瘤出芽，推动CRC向更具侵袭性的阶段发展。

原文链接：

EBP50 Depletion and Nuclear β-Catenin Accumulation Engender Aggressive Behavior of Colorectal Carcinoma through Induction of Tumor Budding