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.
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This work was supported by a Grant-in-Aid for Encouragement of Young Scientists (B, 16K19889, Japan) and JSS Young Researcher Award 2014.
MK: data acquisition and analysis, interpretation of data, and drafting the manuscript. HT, DS, NH, MS, MH, and SY: acquisition and interpretation of data, and manuscript revision. TM, SU, CT, DK, and MF: material support and generation of data. YK: study concept and design, study supervision, interpretation of data, and revision of the manuscript. MK: had full access to all data and takes full responsibility for the veracity of the data and statistical analysis.
Conflict of interest
The authors declare that they have no conflict of interest.
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Kanda, M., Tanaka, H., Shimizu, D. et al. SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells. Oncogene 37, 5355–5366 (2018). https://doi.org/10.1038/s41388-018-0335-8
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