The miR-29c-KIAA1199 axis regulates gastric cancer migration by binding with WBP11 and PTP4A3
The miR-29c-KIAA1199 axis regulates gastric cancer migration by binding with WBP11 and PTP4A3
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miR-29c-KIAA1199 轴通过与 WBP11 和 PTP4A3 结合来调节胃癌迁移。
DOI：
10.1038/s41388-018-0642-0
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发表时间：
2019-04-25
期刊：
影响因子：
8
通讯作者：
Xiao, Bin
中科院分区：
文献类型：
--
作者：
Wang, Lina;Yu, Ting;Xiao, Bin
胃癌是我国癌症患者的第二大死因。GC治疗失败的主要原因是转移。因此，确定转移性生物标志物和阐明GC转移过程中涉及的调控机制是重要的。在这里，我们发现KIAA 1199，一种细胞迁移诱导蛋白，在胃癌中显著过表达，并与淋巴结转移和较差的患者生存率相关。此外，KIAA 1199的引入在体外和体内显著促进GC细胞的增殖和迁移，并且抑制KIAA 1199抑制GC细胞的生长和迁移并诱导GC细胞凋亡。细胞迁移是上皮-间充质转化（EMT）的功能结果。在这项研究中，我们发现KIAA 1199的抑制或过表达通过KIAA 1199与WW结构域结合蛋白11（WBP 11）和蛋白酪氨酸磷酸酶IVA型成员3（PTP 4A 3）的结合以及随后激活FGFR 4/Wnt/β-连环蛋白和EGFR信号通路来调节E-钙粘蛋白和N-钙粘蛋白的表达。更重要的是，WBP 11或PTP 4A 3的异位表达阻断了KIAA 1199对GC细胞增殖和迁移的刺激作用。与此同时，我们证明KIAA 1199是miR-29 c-3 p的靶基因，并且miR-29 c-3 p过表达通过抑制KIAA 1199和Wnt/β-连环蛋白和EGFR信号通路中几种关键蛋白的表达，导致体外和体内GC细胞迁移减少（例如，WBP 11、FGFR 4和PTP 4A 3）。综上所述，这些数据表明，KIAA 1199通过激活EMT相关信号通路促进GC转移，miR-29 c-3 p通过调节KIAA 1199表达和激活FGFR 4/Wnt/β-连环蛋白和EGFR信号通路在体外和体内调节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。
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/beta-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/beta-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/beta-catenin and EGFR signaling pathways. These findings provide a new understanding of GC development and progression and may provide novel therapeutic strategies for GC.