Synbindin in Extracellular Signal-Regulated Protein Kinase Spatial Regulation and Gastric Cancer Aggressiveness

Abstract

Background

The molecular mechanisms that control the aggressiveness of gastric cancer (GC) remain poorly defined. Here we show that synbindin contributes to the aggressiveness of GC by activating extracellular signal-regulated protein kinase (ERK) signaling on the Golgi apparatus.

Methods

Expression of synbindin was examined in normal gastric mucosa (n = 44), intestinal metaplastic gastric mucosa (n = 66), and GC tissues (n=52), and the biological effects of synbindin on tumor growth and ERK signaling were detected in cultured cells, nude mice, and human tissue samples. The interaction between synbindin and mitogen-activated protein kinase kinase (MEK1)/ERK was determined by immunofluorescence and fluorescence resonance energy transfer assays. The transactivation of synbindin by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was detected using luciferase reporter assay and chromatin immunoprecipitation.

Results

High expression of synbindin was associated with larger tumor size (120.8 vs 44.8cm ³ ; P = .01), advanced tumor node metastasis (TNM) stage ( P = .003), and shorter patient survival (hazard ratio = 1.51; 95% confidence interval [CI] = 1.01 to 2.27; P = .046). Synbindin promotes cell proliferation and invasion by activating ERK2 on the Golgi apparatus, and synbindin is directly transactivated by NF-κB. Synbindin expression level was statistically significantly higher in human GCs with activated ERK2 than those with low ERK2 activity (intensity score of 11.5, 95% CI = 10.4 to 12.4 vs intensity score of 4.6, 95% CI 3.9 to 5.3; P < .001). Targeting synbindin in xenograft tumors decreased ERK2 phosphorylation and statistically significantly reduced tumor volume (451.2mm ³ , 95% CI = 328.3 to 574.1 vs 726.1mm ³ , 95% CI = 544.2 to 908.2; P = .01).

Conclusions

Synbindin contributes to malignant phenotypes of GC by activating ERK on the Golgi, and synbindin is a potential biomarker and therapeutic target for GC.