Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Institution of Gastroenterology, Zhejiang University, Hangzhou, China.
FASEB J. 2020 Feb;34(2):2161-2172. doi: 10.1096/fj.201901372RR. Epub 2020 Jan 2.
Gastric cancer (GC) patients with metastasis had limited treatment options and dismal outcome. We have previously reported the aberrant expression of Zic family member 1 (Zic1) in GC. However, the functional roles and underlying mechanism of Zic1 in GC metastasis remain unknown. Here, we demonstrate that lower expression of Zic1 was correlated with more lymph node metastasis and poor outcome of GC patients. Ectopic expression of Zic1 suppressed both lung metastasis and peritoneal tumor dissemination of GC in mice. The metastatic suppressing ability of Zic1 was mediated by regulating the process of cell invasion, adhesion and epithelial-mesenchymal transition (EMT). Mechanistically, Zic1 could downregulate Wnt targets including c-Myc and Cyclin D1 by inhibiting LEF transcriptional activity in GC cells. Notably, Zic1 was inversely related to the expression of Cyclin D1 in GC tissues tested. In addition, Zic1 could physically interact with β-catenin/transcription factor 4 (TCF4) and disrupt their complex formation, while not affecting β-catenin nuclear localization. Collectively, our study indicated that Zic1 suppressed GC metastasis through attenuating Wnt/β-catenin signaling and the EMT process. Our work may provide novel therapeutic strategies for the metastasis of GC.
胃癌（GC）患者发生转移后，治疗选择有限，预后较差。我们之前曾报道过锌指蛋白家族成员 1（Zic1）在 GC 中的异常表达。然而，Zic1 在 GC 转移中的功能作用及其潜在机制仍不清楚。本研究表明，Zic1 表达水平降低与 GC 患者淋巴结转移更多和预后不良相关。在小鼠中异位表达 Zic1 可抑制 GC 的肺转移和腹膜肿瘤播散。Zic1 的转移抑制能力是通过调节细胞侵袭、黏附和上皮间质转化（EMT）过程来介导的。在 GC 细胞中，Zic1 通过抑制 LEF 的转录活性，下调 Wnt 靶基因包括 c-Myc 和 Cyclin D1。值得注意的是，在检测的 GC 组织中，Zic1 的表达与 Cyclin D1 的表达呈负相关。此外，Zic1 可以与β-连环蛋白/转录因子 4（TCF4）发生物理相互作用，破坏它们的复合物形成，而不影响β-连环蛋白的核定位。总之，本研究表明，Zic1 通过抑制 Wnt/β-连环蛋白信号通路和 EMT 过程抑制 GC 转移。我们的工作可能为 GC 的转移提供新的治疗策略。
