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

• Published in: JNCI : Journal of the National Cancer Institute Vol. 105; no. 22; pp. 1738 - 1749
• Main Authors: XUAN KONG, JIN QIAN, WEIPING ZOU, JIE XU, FANG, Jing-Yuan, CHEN, Li-Sha, WANG, Ying-Chao, WANG, Ji-Lin, HAOYAN CHEN, WENG, Yu-Rong, ZHAO, Shu-Liang, JIE HONG, CHEN, Ying-Xuan
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 20.11.2013
• Subjects: Animals; Biological and medical sciences; Cell Line, Tumor; Chromatin Immunoprecipitation; Flow Cytometry; Fluorescence Resonance Energy Transfer; Fluorescent Antibody Technique; Gastric Mucosa - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Golgi Apparatus - enzymology; Golgi Apparatus - metabolism; Heterografts; Humans; Kaplan-Meier Estimate; Luciferases; Luminescent Agents; MAP Kinase Kinase 1 - metabolism; MAP Kinase Signaling System; Medical sciences; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1 - metabolism; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; NF-kappa B - metabolism; Odds Ratio; Phosphorylation; Protein Array Analysis; Retrospective Studies; Stomach Neoplasms - enzymology; Stomach Neoplasms - metabolism; Stomach Neoplasms - mortality; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transcriptional Activation; Tumors; Up-Regulation; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; Human; Cancerology; Extracellular signal-regulated protein kinase; Enzyme; Transferases; Mitogen-activated protein kinase; Digestive diseases; Malignancy; Malignant tumor; Stomach cancer; Cancer; Gastric disease
• DOI: 10.1093/jnci/djt271
• ISSN: 0027-8874

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