Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Cancer Center, Zhejiang University, Hangzhou, China.
Oncogene. 2022 Feb;41(6):770-781. doi: 10.1038/s41388-021-02119-3. Epub 2021 Nov 29.
DGC is a particular aggressive malignancy with poor prognosis. Recent omics studies characterized DGC with CDH1/E-cadherin loss and EMT-signatures. However, the underlying mechanisms for maintaining the aggressive behavior and molecular features of DGC remain unclear. Here, we find that intermediate filaments KRT17 is significantly lower in DGC tissues than that in intestinal gastric cancer tissues and associated with poor prognosis of DGC. We demonstrate that downregulation of KRT17 induces E-cadherin loss, EMT changes, and metastasis behaviors of GC cells. Mechanistically, the loss of intermediate filaments KRT17 induces reorganization of cytoskeleton, further activates YAP signaling, and increases IL6 expression, which contributes to the enhanced metastasis ability of GC cells. Together, these results indicate that KRT17/YAP/IL6 axis contributes to maintaining E-cadherin loss, EMT feature, and metastasis of DGC, providing a new insight into the role of aberrant intermediate filaments in DGC malignancy.
弥漫型胃癌（DGC）是一种侵袭性很强且预后较差的恶性肿瘤。最近的组学研究表明，DGC 存在 CDH1/E-钙黏蛋白丢失和 EMT 特征。然而，维持 DGC 侵袭性行为和分子特征的潜在机制仍不清楚。本研究发现，与肠型胃癌组织相比，DGC 组织中细胞角蛋白 17（KRT17）显著降低，并与 DGC 的不良预后相关。研究表明，下调 KRT17 可诱导 E-钙黏蛋白丢失、EMT 改变和 GC 细胞的转移行为。机制上，中间丝 KRT17 的缺失诱导细胞骨架重排，进一步激活 YAP 信号通路，增加 IL6 的表达，从而增强 GC 细胞的转移能力。综上所述，这些结果表明 KRT17/YAP/IL6 轴有助于维持 DGC 的 E-钙黏蛋白丢失、EMT 特征和转移，为异常中间丝在 DGC 恶性肿瘤中的作用提供了新的见解。
