MST4 Predicts Poor Prognosis And Promotes Metastasis By Facilitating Epithelial-Mesenchymal Transition In Gastric Cancer
MST4 Predicts Poor Prognosis And Promotes Metastasis By Facilitating Epithelial-Mesenchymal Transition In Gastric Cancer
复制标题
MST4 通过促进胃癌上皮-间质转化来预测不良预后并促进转移
DOI：
10.2147/cmar.s219689
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发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Lei, Xiong
中科院分区：
文献类型：
--
作者：
Li, Taiyuan;Deng, Li;Lei, Xiong
背景：转移是胃癌（GC）相关死亡的主要原因。更好地了解胃癌转移机制将提供新的诊断标志物和治疗靶点。虽然有报道称哺乳动物不育-20样激酶4 （MST4）在其他肿瘤中发挥致瘤作用，但MST4在胃癌中的预后价值和生物学作用尚不清楚。方法：采用TCGA数据库分析胃癌组织中MST4的表达水平。然后采用Western blot和PCR检测MST4在胃癌组织和细胞系中的表达，采用免疫组化方法检测胃癌组织中MST4蛋白的表达，并分析其与胃癌患者临床病理参数及预后的相关性。此外，通过体外和体内实验，探讨了MST4在GC中的生物学功能及其分子机制。结果：MST4在胃癌组织和细胞系中表达显著上调。MST4高表达与淋巴结转移、淋巴血管侵袭等侵袭性临床病理指标相关（均P < 0.05）。MST4高表达胃癌患者的总生存期（OS）和无病生存期（DFS）均短于MST4低表达胃癌患者（P < 0.05）。MST4表达是胃癌患者OS和DFS的独立且显著的危险因素（均P < 0.05）。功能实验结果表明，MST4能促进胃癌细胞在体外的迁移、侵袭和体内的转移。从机制上看，MST4通过激活Ezrin通路，促进胃癌上皮-间质转化（epithelial-mesenchymal transition， EMT），从而促进胃癌转移。进一步研究表明，miR-124-3p表达下调导致胃癌中MST4表达上调。结论：我们的数据表明，MST4通过促进胃癌的上皮-间质转化来预测预后不良并促进转移。因此，我们的研究表明MST4可以作为一种有价值的预后生物标志物和潜在的GC治疗靶点。
Background: Metastasis is the main cause for gastric cancer (GC)-related deaths. Better understanding of GC metastatic mechanism would provide novel diagnostic markers and therapeutic targets. Though it has been reported that mammalian sterile-20-like kinase 4 (MST4) exerts the oncogenic role in other tumors, the prognostic value and biological role of MST4 in GC are still unknown.Methods: The expression level of MST4 in GC was analyzed by using TCGA database. Then, Western blot and polymerase chain reaction (PCR) were used to determine the MST4 expression in GC tissues and cell lines Immunohistochemistry was performed to investigate the expression of proteins in human GC tissues, and its correlation with clinicopathologic parameters as well as the prognosis for patients with GC was analyzed. In addition, the biological function and its molecular mechanism of MST4 in GC were investigated by in vitro and in vivo assays.Results: It demonstrated that MST4 expression was significantly upregulated in GC tissues and cell lines. High expression of MST4 was correlated with aggressive clinicopathological parameters such as lymph node metastasis, lymphovascular invasion (all P < 0.05). GC patients with high MST4 expression had both shorter overall survival (OS) and disease-free survival (DFS) than those with low MST4 expression (all P < 0.05). MST4 expression was an independent and significant risk factor for OS and DFS of GC patients (all P < 0.05). Results of functional experiments showed that MST4 could promote GC cells migration, invasion in vitro and metastasis in vivo. In terms of mechanism, MST4 promoted metastasis by facilitating epithelial-mesenchymal transition (EMT) through activating Ezrin pathway in GC. Further studies indicate that down-regulated miR-124-3p expression contributes to upregulated MST4 expression in GC.Conclusion: Our data showed that MST4 predicts poor prognosis and promotes metastasis by facilitating epithelial-mesenchymal transition in GC. Therefore, our study suggests that MST4 can be used as a valuable prognostic biomarker and a potential therapeutic target in GC.