Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway

Oncogene. 2003 Mar 13;22(10):1517-27. doi: 10.1038/sj.onc.1206226.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Carcinogenicity Tests
  • Cell Division / genetics
  • Cervix Uteri / metabolism
  • Chick Embryo
  • Culture Media, Conditioned / pharmacology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Interleukin-6 / physiology*
  • Lymphokines / drug effects
  • Lymphokines / genetics
  • Lymphokines / metabolism*
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic
  • Reference Values
  • STAT3 Transcription Factor
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Tumor Cells, Cultured
  • Up-Regulation
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology*
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Antibodies, Monoclonal
  • Culture Media, Conditioned
  • DNA-Binding Proteins
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-6
  • Lymphokines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Trans-Activators
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors