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Synbindin in extracellular signal-regulated protein kinase spatial regulation and gastric cancer aggressiveness
Xuan Kong1, Jin Qian, Li-Sha Chen
1Affiliations of authors: State Key Laboratory for Oncogenes and Related Genes, Shanghai, China (XK, JQ, L-SC, Y-CW, J-LW, HC, Y-RW, S-LZ, JH, Y-XC, JX, J-YF); Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai Jiao-Tong University School of Medicine, Shanghai, China (XK, JQ, L-SC, Y-CW, J-LW, HC, Y-RW, S-LZ, JH, Y-XC, JX, J-YF); Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Shanghai, China (XK, JQ, L-SC, Y-CW, J-LW, HC, Y-RW, S-LZ, JH, Y-XC, JX, J-YF); Department of Surgery, University of Michigan, Ann Arbor, MI (WZ).
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 44.8 cm(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.
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