EXOC4 Promotes Diffuse-Type Gastric Cancer Metastasis via Activating FAK Signal.
EXOC4 Promotes Diffuse-Type Gastric Cancer Metastasis via Activating FAK Signal.
复制标题
EXOC4通过激活FAK信号促进弥漫型胃癌转移
DOI：
10.1158/1541-7786.mcr-21-0441
复制
发表时间：
2022-07-06
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
弥漫型胃癌（diffuse-type gastric cancer，DGC）是一种复发率高、转移率高、临床预后差的恶性肿瘤，其复发机制尚不清楚。通过采用LC/MS-MS蛋白质组学方法，我们确定了与未复发的DGC相比，复发的DGC中的外囊复合物组分4（EXOC 4）显著上调。EXOC 4的高表达与DGC患者的肿瘤转移和不良预后相关。此外，EXOC 4促进细胞迁移和侵袭以及DGC细胞的肿瘤转移。从机制上讲，EXOC 4通过刺激整合素α5/β1/EGF的分泌并增强粘着斑激酶（FAK）与整合素或EGFR的相互作用来调节Y397位点粘着斑激酶（FAK）的磷酸化。FAK抑制剂VS-4718逆转了由EXOC 4过表达介导的转移，并抑制了源自具有高EXOC 4表达的DGC的患者来源的异种移植物的肿瘤生长。EXOC 4-FAK轴可能是EXOC 4高表达的DGC患者的潜在治疗靶点。EXOC 4-FAK轴促进DGC转移，可能成为DGC患者潜在的治疗靶点。
In comparison with intestinal-type gastric cancer, diffuse-type gastric cancer (DGC) is more likely to recur, metastasize, and exhibit worse clinical outcomes; however, the underlying mechanism of DGC recurrence remains elusive. By employing an LC/MS-MS proteomic approach, we identified that exocyst complex component 4 (EXOC4) was significantly upregulated in DGC with recurrence, compared to those with nonrecurrence. High expression of EXOC4 was correlated with tumor metastasis and poor prognosis in patients with DGC. Moreover, EXOC4 promoted cell migration and invasion as well as the tumor metastasis of DGC cells. Mechanistically, EXOC4 regulated the phosphorylation of focal adhesion kinase (FAK) at Y397 sites by stimulating the secretion of integrin α5/β1/EGF and enhancing the interaction of FAK and integrin or EGFR. The FAK inhibitor VS-4718 reversed the metastasis mediated by EXOC4 overexpression and suppressed the tumor growth of patient-derived xenografts derived from DGC with high EXOC4 expression. The EXOC4–FAK axis could be a potential therapeutic target for patients with DGC with high expression of EXOC4. The EXOC4–FAK axis promoted DGC metastasis and could be a potential therapeutic target for patients with DGC.
影响因子：
2.6
作者：
Holmes K;Egan B;Swan N;O'Morain C
通讯作者：
O'Morain C