title: N-myc downstream-regulated gene 1 promotes tumor inflammatory angiogenesis through JNK activation and autocrine loop of interleukin-1α by human gastric cancer cells.
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.
authors.affiliation: From the Department of Pharmaceutical Oncology and; the St. Mary's Hospital, Kurume 830-8543.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: From the Department of Pharmaceutical Oncology and.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Watari
authors.affiliation: From the Department of Pharmaceutical Oncology and.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: From the Department of Pharmaceutical Oncology and.
authors.forename: Manami
authors.initials: M
authors.lastname: Uba
authors.affiliation: From the Department of Pharmaceutical Oncology and.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ureshino
authors.affiliation: the Department of Diagnostic Pathology, Kurume University Hospital, Kurume 830-0011.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kawahara
authors.affiliation: the Department of Diagnostic Pathology, Kurume University Hospital, Kurume 830-0011.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Abe
authors.affiliation: the Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu 807-8555, and.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.affiliation: the Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.affiliation: Laboratory of Molecular Cancer Biology, Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582.
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.affiliation: From the Department of Pharmaceutical Oncology and. Electronic address: mono@phar.kyushu-u.ac.jp.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D019743:Chemokines, CXC; D053582:Interleukin-1alpha; D015847:Interleukin-4; D047908:Intracellular Signaling Peptides and Proteins; D048670:MAP Kinase Kinase 4; D020781:Matrix Metalloproteinase 1; D053509:Matrix Metalloproteinase 13; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C508584:IL1A protein, human; C508598:IL4 protein, human; C467484:VEGFA protein, human; C467480:vascular endothelial growth factor A, mouse; C507081:Mmp13 protein, mouse; C522360:MMP1 protein, human
keywords: AP1 Transcription Factor; Angiogenesis; Gastric Cancer; Inflammation; Interleukin; N-myc Downstream-regulated Gene 1