SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells
SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells
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DOI：
10.1038/s41388-018-0335-8
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发表时间：
2018-09-27
期刊：
影响因子：
8
通讯作者：
Kodera, Yasuhiro
中科院分区：
文献类型：
--
作者：
Kanda, Mitsuro;Tanaka, Haruyoshi;Kodera, Yasuhiro
肝转移仍然是胃癌治疗中的一个严重问题。我们的目的是通过转录组分析确定介导胃癌肝转移的分子，并评估其作为诊断标志物和治疗靶点的潜力。在体外实验和小鼠异种移植模型中评估了使用基因组编辑敲除相关分子的效果。确定候选分子在300对胃组织中的表达水平，以评估差异表达的基因是否预测肝复发、转移或两者兼而有之。转录组数据确定了突触结合蛋白VII（SYT 7）在具有肝转移的GC组织中的过表达。其在GC细胞系中的表达是高的，特别是在那些表现出分化表型的GC细胞系中，并且与SNAI 1和TGFB 3的表达正相关，与RGS 2的表达负相关。SYT 7基因敲除可抑制GC细胞的增殖，表现为凋亡增加，半胱天冬酶活化，线粒体膜电位丧失，G2/M期细胞周期阻滞，细胞迁移、侵袭和粘附减弱。SYT 7敲除细胞的致瘤性在皮下转移的小鼠模型中适度降低，其中BCL 2和HIF 1A的水平降低，并且在肝转移的模型中更显著地减弱。原发性胃癌组织中SYT 7水平与肝复发、转移和不良预后显著相关。SYT 7代表了用于预测和监测来自GC的肝转移的工具，并且是有希望的治疗靶点。
Liver metastasis remains a serious problem in the management of gastric cancer (GC). Our aims were to identify through transcriptome analysis a molecule that mediates hepatic metastasis in GC, and to evaluate its potential as a diagnostic marker and a therapeutic target. The effects of knocking out a relevant molecule using genome editing were evaluated in vitro experiments and in mouse xenograft models. Expression levels of candidate molecule in 300 pairs of gastric tissues were determined to assess whether differentially expressed genes predicted hepatic recurrence, metastasis, or both. Transcriptome data identified the overexpression of synaptotagmin VII (SYT7) in GC tissues with hepatic metastasis. Its expression in the GC cell lines was high, particularly in those that exhibited a differentiated phenotype, and positively correlated with the expression of SNAI1 and TGFB3, and inversely with RGS2. SYT7 knockout inhibited the proliferation of GC cells, indicated by increased apoptosis with activated caspase and loss of mitochondria membrane potential, G2/M cell-cycle arrest and attenuated cell migration, invasion, and adhesion. The tumorigenicity of SYT7-knockout cells was moderately reduced in a mouse model of subcutaneous metastasis in which the levels of BCL2 and HIF1A were decreased and was more strikingly attenuated in a model of hepatic metastasis. The SYT7 levels in the primary GC tissues were significantly associated with hepatic recurrence, metastasis, and adverse prognosis. SYT7 represents a tool for prediction and monitoring of hepatic metastasis from GC as well as being a promising therapeutic target.