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 44.8 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.

• Authors: Xuan Kong, Jin Qian, Li-Sha Chen, Ying-Chao Wang, Ji-Lin Wang, Haoyan Chen, Yu-Rong Weng, Shu-Liang Zhao, Jie Hong, Ying-Xuan Chen, Weiping Zou, Jie Xu, Jing-Yuan Fang
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 105 Issue 22 Pg. 1738-49 (Nov 20 2013) ISSN: 1460-2105 [Electronic] United States
• PMID: 24104608 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Luminescent Agents
• NF-kappa B
• Nerve Tissue Proteins
• TRAPPC4 protein, human
• Trappc4 protein, mouse
• Vesicular Transport Proteins
• Luciferases
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• MAP Kinase Kinase 1

Topics

• Animals
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Flow Cytometry
• Fluorescence Resonance Energy Transfer
• Fluorescent Antibody Technique
• Gastric Mucosa (metabolism)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Golgi Apparatus (enzymology, metabolism)
• Heterografts
• Humans
• Kaplan-Meier Estimate
• Luciferases
• Luminescent Agents
• MAP Kinase Kinase 1 (metabolism)
• MAP Kinase Signaling System
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinase 1 (metabolism)
• NF-kappa B (metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Odds Ratio
• Phosphorylation
• Protein Array Analysis
• Retrospective Studies
• Stomach Neoplasms (enzymology, metabolism, mortality, pathology)
• Transcriptional Activation
• Up-Regulation
• Vesicular Transport Proteins (genetics, metabolism)