Abstract
The expression of N-myc downstream-regulated gene 1 (NDRG1) was significantly correlated with tumor angiogenesis and malignant progression together with poor prognosis in gastric cancer. However, the underlying mechanism for the role of NDRG1 in the malignant progression of gastric cancer remains unknown. Here we examined whether and how NDRG1 could modulate tumor angiogenesis by human gastric cancer cells. We established NU/Cap12 and NU/Cap32 cells overexpressing NDRG1 in NUGC-3 cells, which show lower tumor angiogenesis in vivo. Compared with parental NU/Mock3, NU/Cap12, and NU/Cap32 cells: 1) induced higher tumor angiogenesis than NU/Mock3 cells accompanied by infiltration of tumor-associated macrophages in mouse dorsal air sac assay and Matrigel plug assay; 2) showed much higher expression of CXC chemokines, MMP-1, and the potent angiogenic factor VEGF-A; 3) increased the expression of the representative inflammatory cytokine, IL-1α; 4) augmented JNK phosphorylation and nuclear expression of activator protein 1 (AP-1). Further analysis demonstrated that knockdown of AP-1 (Jun and/or Fos) resulted in down-regulation of the expression of VEGF-A, CXC chemokines, and MMP-1, and also suppressed expression of IL-1α in NDRG1-overexpressing cell lines. Treatment with IL-1 receptor antagonist (IL-1ra) resulted in down-regulation of JNK and c-Jun phosphorylation, and the expression of VEGF-A, CXC chemokines, and MMP-1 in NU/Cap12 and NU/Cap32 cells. Finally, administration of IL-1ra suppressed both tumor angiogenesis and infiltration of macrophages by NU/Cap12 in vivo. Together, activation of JNK/AP-1 thus seems to promote tumor angiogenesis in relationship to NDRG1-induced inflammatory stimuli by gastric cancer cells.
Keywords:
AP1 Transcription Factor; Angiogenesis; Gastric Cancer; Inflammation; Interleukin; N-myc Downstream-regulated Gene 1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Chemokines, CXC / genetics
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Chemokines, CXC / metabolism
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Enzyme Activation / genetics
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Inflammation / genetics
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Inflammation / metabolism
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Inflammation / pathology
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Interleukin-1alpha / genetics
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Interleukin-1alpha / metabolism*
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Interleukin-4 / genetics
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Interleukin-4 / metabolism
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism*
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Macrophages / metabolism
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Macrophages / pathology
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Male
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Matrix Metalloproteinase 1 / genetics
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Matrix Metalloproteinase 1 / metabolism
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Matrix Metalloproteinase 13 / genetics
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Matrix Metalloproteinase 13 / metabolism
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Mice
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Mice, Inbred BALB C
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism*
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Neovascularization, Pathologic / pathology
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Phosphorylation / genetics
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism*
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Stomach Neoplasms / pathology
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Cell Cycle Proteins
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Chemokines, CXC
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IL1A protein, human
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IL4 protein, human
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Interleukin-1alpha
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Intracellular Signaling Peptides and Proteins
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N-myc downstream-regulated gene 1 protein
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Transcription Factor AP-1
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Interleukin-4
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MAP Kinase Kinase 4
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Matrix Metalloproteinase 13
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Mmp13 protein, mouse
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MMP1 protein, human
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Matrix Metalloproteinase 1