Zic1 suppresses gastric cancer metastasis by regulating Wnt/β-catenin signaling and epithelial-mesenchymal transition
Zic1 suppresses gastric cancer metastasis by regulating Wnt/β-catenin signaling and epithelial-mesenchymal transition
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Zic1通过调节Wnt/β-catenin信号传导和上皮间质转化抑制胃癌转移
DOI：
10.1096/fj.201901372rr
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发表时间：
2020-02-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Liangjing
中科院分区：
文献类型：
--
作者：
Ge, Qiwei;Hu, Yingying;Wang, Liangjing
胃癌（GC）转移患者的治疗选择有限，预后不良。我们之前曾报道过GC中Zic家族成员1（Zic 1）的异常表达。然而，Zic 1在胃癌转移中的功能作用和潜在机制尚不清楚。在这里，我们证明Zic 1的低表达与胃癌患者的淋巴结转移和预后不良有关。Zic 1的异位表达抑制了小鼠胃癌的肺转移和腹膜肿瘤播散。Zic 1通过调节细胞的侵袭、粘附和上皮-间质转化（EMT）过程来抑制肿瘤的转移。Zic 1可通过抑制胃癌细胞中LEF的转录活性下调Wnt靶点，包括c-Myc和Cyclin D1。值得注意的是，Zic 1与所测试的GC组织中Cyclin D1的表达呈负相关。此外，Zic 1可以与β-连环蛋白/转录因子4（TCF 4）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。总的来说，我们的研究表明Zic 1通过减弱Wnt/β-catenin信号传导和EMT过程抑制GC转移。我们的工作可能为胃癌的转移提供新的治疗策略。
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 beta-catenin/transcription factor 4 (TCF4) and disrupt their complex formation, while not affecting beta-catenin nuclear localization. Collectively, our study indicated that Zic1 suppressed GC metastasis through attenuating Wnt/beta-catenin signaling and the EMT process. Our work may provide novel therapeutic strategies for the metastasis of GC.