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

Oncogene volume 22, pages 1517–1527 (2003)Cite this article

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.

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Acknowledgements

We thank the National Science Council of the Republic of China for financially supporting this research under Contract No. NSC-90-2314-B-002-208.

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Authors and Affiliations

  1. Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan

    Lin-Hung Wei & Chang-Yao Hsieh

  2. Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan

    Min-Liang Kuo & Chia-Hung Chou

  3. Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan

    Chi-An Chen, Kuo-Bau Lai, Chien-Nan Lee & Chang-Yao Hsieh

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Correspondence to Chang-Yao Hsieh.

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Wei, LH., Kuo, ML., Chen, CA. et al. Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene 22, 1517–1527 (2003). https://doi.org/10.1038/sj.onc.1206226

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