National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, 400038, Chongqing, China.
Department of Pharmacy, Southwest Hospital, Third Military Medical University, 400038, Chongqing, China.
Oncogene. 2019 Apr;38(17):3134-3150. doi: 10.1038/s41388-018-0642-0. Epub 2019 Jan 9.
Gastric cancer (GC) is the second leading cause of death among patients with cancer in China. The primary reason of GC treatment failure is metastasis. Therefore, identifying metastatic biomarkers and clarifying the regulatory mechanisms involved in the GC metastatic process are important. Here, we found that KIAA1199, a cell migration-inducing protein, was significantly overexpressed in GC and correlated with lymph node metastasis and poorer patient survival. Additionally, the introduction of KIAA1199 dramatically promoted GC cell proliferation and migration in vitro and in vivo, and the inhibition of KIAA1199 suppressed GC cell growth and migration and induced GC cell apoptosis. Cell migration is a functional consequence of the epithelial-mesenchymal transition (EMT). In this study, we found that KIAA1199 inhibition or overexpression regulated the expression of E-cadherin and N-cadherin through KIAA1199 binding to WW domain binding protein 11 (WBP11) and protein tyrosine phosphatase type IVA, member 3 (PTP4A3) and through the subsequent activation of the FGFR4/Wnt/β-catenin and EGFR signaling pathways. More importantly, ectopic expression of WBP11 or PTP4A3 blocked the stimulatory effects of KIAA1199 on GC cell proliferation and migration. Meanwhile, we illustrated that KIAA1199 was a target gene of miR-29c-3p and that miR-29c-3p overexpression led to decreased migration of GC cells in vitro and in vivo by suppressing the expression of KIAA1199 and several key proteins in the Wnt/β-catenin and EGFR signaling pathways (e.g., WBP11, FGFR4, and PTP4A3). Taken together, these data demonstrate that KIAA1199 promotes GC metastasis by activating EMT-related signaling pathways and that miR-29c-3p regulates GC cell migration in vitro and in vivo by regulating KIAA1199 expression and activating the FGFR4/Wnt/β-catenin and EGFR signaling pathways. These findings provide a new understanding of GC development and progression and may provide novel therapeutic strategies for GC.
胃癌（GC）是中国癌症患者死亡的第二大主要原因。GC 治疗失败的主要原因是转移。因此，鉴定转移的生物标志物并阐明参与 GC 转移过程的调节机制非常重要。在这里，我们发现细胞迁移诱导蛋白 KIAA1199 在 GC 中显著过表达，并且与淋巴结转移和患者生存不良相关。此外，引入 KIAA1199 可在体外和体内显著促进 GC 细胞增殖和迁移，而抑制 KIAA1199 则抑制 GC 细胞生长和迁移并诱导 GC 细胞凋亡。细胞迁移是上皮-间充质转化（EMT）的功能后果。在这项研究中，我们发现 KIAA1199 通过与 WW 结构域结合蛋白 11（WBP11）和蛋白酪氨酸磷酸酶类型 IVA，成员 3（PTP4A3）结合来调节 E-钙粘蛋白和 N-钙粘蛋白的表达，并通过随后激活 FGFR4/Wnt/β-catenin 和 EGFR 信号通路。更重要的是，WBP11 或 PTP4A3 的异位表达阻断了 KIAA1199 对 GC 细胞增殖和迁移的刺激作用。同时，我们说明了 KIAA1199 是 miR-29c-3p 的靶基因，并且 miR-29c-3p 通过抑制 KIAA1199 和 Wnt/β-catenin 和 EGFR 信号通路中的几个关键蛋白（例如，WBP11、FGFR4 和 PTP4A3）的表达，导致体外和体内 GC 细胞迁移减少。总之，这些数据表明 KIAA1199 通过激活 EMT 相关信号通路促进 GC 转移，并且 miR-29c-3p 通过调节 KIAA1199 表达和激活 FGFR4/Wnt/β-catenin 和 EGFR 信号通路来调节体外和体内 GC 细胞迁移。这些发现为 GC 的发生和发展提供了新的认识，并可能为 GC 提供新的治疗策略。
