IDDF2018-ABS-0117 Identification of molecules driving hepatic metastasis formation of gastric cancer cells

Abstract

Background Hepatic metastasis and relapse contribute to the high incidence of gastric cancer (GC)-related fatalities and represent a frequent and crucial problem for oncologists. The aim of this study was to identify and explore diagnostic biomarkers and molecular targets to predict and treat hepatic metastases. Methods Transcriptome and bioinformatics analyses were conducted using tissues from patients who had GC with synchronous hepatic metastasis to identify a candidate molecule that specifically mediates hepatic metastasis of GC. Stable knockout cells were established by genome editing using the CRISPR-CAS9 system. In vitro analyses including proliferation, apoptosis, migration, invasion and adhesion assays were performed to evaluate the effect of knockout. Mouse subcutaneous xenograft and liver metastasis models were used to evaluate influences of knockout on tumorigenicity and formation of hepatic metastasis. mRNA levels of the candidate molecule were determined in the gastric tissues of 200 patients with GC to assess whether differential gene expression predicted patient prognosis. Results Synaptotagmin VII (SYT7) was identified as a candidate biomarker for hepatic metastasis in GC. GC cell lines exhibited differential SYT7 expression levels and the mRNAs encoding SNAI1 and TGFB3 was expressed at levels that correlated significantly with those of SYT7 mRNA, whereas the expression levels of RGS2 mRNA correlated inversely with those of SYT7. The proliferation, invasion, adhesion and migration abilities of stable SYT7-knockout GC cells were significantly reduced compared to MKN control cells. Stable SYT7-knockout GC cells showed significantly more annexin V positive cells in comparison to the MKN1 cells. Tumorigenicity of GC cells in mouse subcutaneous xenograft models was significantly decreased in stable SYT7-knockout GC cells accompanying reduced Bcl-2 and HIF-1a protein expression in subcutaneous tumours. Tumour growth after portal injection of cells was significantly decreased in stable SYT7-knockout GC cells. High SYT7 expression in clinical GC tissues was associated with shortened overall and disease-free survival. Conclusions SYT7 represents a promising target for treatment of hepatic metastasis of GC.