Interleukin-6 increases vascular endothelial growth factor and angiogenesis in gastric carcinoma.
Interleukin-6 (IL-6) is a proinflammatory cytokine associated with the disease status of gastric carcinoma (GC). Vascular endothelial growth factor (VEGF) is a potent tumor angiogenic factor in GC. In this study, we attempted to clarify whether IL-6 can regulate VEGF and angiogenesis in GC. GC samples from 54 surgical specimens were subjected to immunohistochemical examination of IL-6, VEGF, and tumor microvessels, and results showed that IL-6 was positively correlated with VEGF expression and tumor vasculature. We determined VEGF expression in four GC cell lines by ELISA, revealing that GC cells can produce significant amount of VEGF with increasing dose and duration of IL-6 stimulation. Next, a luciferase reporter gene assay was employed to determine the signaling pathway driving the VEGF promoter by IL-6, which showed that the JAK/STAT pathway is involved in the stimulation of VEGF gene expression. The effects of IL-6 on angiogenesis in vitro and in vivo were evaluated by HUVEC studies and the Matrigel plug assay, respectively. Results showed that IL-6 effectively promoted HUVEC proliferation and tube formation in vitro and Matrigel plug vascularization in vivo, primarily by inducing VEGF in GC. This study provides evidence that the multifunctional cytokine, IL-6, may induce VEGF expression which increases angiogenesis in gastric carcinogenesis.
Huang
Shih-Pei
SP
Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Wu
Ming-Shiang
MS
Shun
Chia-Tung
CT
Wang
Hsiu-Po
HP
Lin
Ming-Tsan
MT
Kuo
Min-Liang
ML
Lin
Jaw-Town
JT
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004730:Endothelium, Vascular; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D053613:Janus Kinase 1; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000098:blood supply* / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D042442:Vascular Endothelial Growth Factors / Q000032:analysis / Q000187:drug effects / Q000235:genetics*
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D042442:Vascular Endothelial Growth Factors; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1