Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway
Journal
Oncogene
Journal Volume
22
Journal Issue
10
Pages
1517-1527
Date Issued
2003
Author(s)
Abstract
Interleukin-6 (IL-6) has received particular attention in the pathogenesis of cervical cancer, although the underlying mechanism remains elusive. This study revealed that IL-6 promotes in vivo tumor growth of human cervical cancer C33A cells, but does not substantially alter their in vitro growth kinetics. The in vivo angiogenic assays showed that IL-6 increases angiogenic activity in human cervical cancer cells, an effect that is specifically associated with upregulation of vascular endothelial growth factor (VEGF). Also, using anti-VEGF antibody to block VEGF function significantly inhibited IL-6-mediated angiogenesis and tumor growth in nude mice, strongly supporting the critical role of VEGF in the IL-6-mediated cervical tumorigenesis. Accordingly, the signaling pathway downstream of IL-6/ IL-6R responsible for the regulation of VEGF was investigated. Notably, pharmacological inhibition of PI3-K or MAPK failed to inhibit IL-6-mediated transcriptional upregulation of VEGF. Meanwhile, blocking STAT3 pathway with dominant-negative mutant STAT3D effectively abolished IL-6-induced VEGF mRNA. In transient transfections, a luciferase reporter construct containing the full-length 1.5-kb VEGF promoter or a 1.2-kb fragment lacking the known hypoxic-response element also exhibited the same degree of response to IL-6. Additionally, transient transfection of STAT3D downregulated the 1.2-kb VEGF promoter luciferase reporter stimulated by IL-6. Based on the above phenomenon combined with the concomitant increased tumor expression of IL-6 and VEGF in cervical cancer tissues, we conclude that IL-6 may promote cervical tumorigenesis by activating VEGF-mediated angiogenesis via a STAT3 pathway.
SDGs
Other Subjects
interleukin 6; interleukin 6 receptor; luciferase; mitogen activated protein kinase; phosphatidylinositol 3 kinase; STAT3 protein; vasculotropin; angiogenesis; animal experiment; animal model; article; cancer growth; controlled study; down regulation; genetic transcription; human; human cell; hypoxia; mouse; nonhuman; nude mouse; priority journal; protein expression; reporter gene; signal transduction; upregulation; uterine cervix cancer; Animals; Antibodies, Monoclonal; Carcinogenicity Tests; Cell Division; Cervix Uteri; Chick Embryo; Culture Media, Conditioned; DNA-Binding Proteins; Endothelial Growth Factors; Enzyme Inhibitors; Female; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-6; Lymphokines; Mice; Mice, Nude; Neovascularization, Pathologic; Reference Values; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Tumor Cells, Cultured; Up-Regulation; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Animalia; Mus musculus
Type
journal article