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Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis

Genes & Dev., 15 July 2007
Vol. 21, Issue 14, p. 1714-1719
DOI: 10.1101/gad.1549407

Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis

  1. Brooke Ancrile,
  2. Kian-Huat Lim, and
  3. Christopher M. Counter1
  1. Department of Pharmacology and Cancer Biology, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA


Ras is mutated to remain in the active oncogenic state in many cancers. As Ras has proven difficult to target therapeutically, we searched for secreted, druggable proteins induced by Ras that are required for tumorigenesis. We found that Ras induces the secretion of cytokine IL6 in different cell types, and that knockdown of IL6, genetic ablation of the IL6 gene, or treatment with a neutralizing IL6 antibody retard Ras-driven tumorigenesis. IL6 appears to act in a paracrine fashion to promote angiogenesis and tumor growth. Inhibiting IL6 may therefore have therapeutic utility for treatment of cancers characterized by oncogenic Ras mutations.

  • Ras
  • oncogene
  • IL6
  • cytokine
  • cancer



B. Ancrile, K.-H. Lim, and C. M. Counter, Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes & Dev. 21, 1714-1719 (2007).

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Z. C. Hartman, G. M. Poage, P. den Hollander, A. Tsimelzon, J. Hill, N. Panupinthu, Y. Zhang, A. Mazumdar, S. G. Hilsenbeck, G. B. Mills et al.
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L. D. Mills, Y. Zhang, R. J. Marler, M. Herreros-Villanueva, L. Zhang, L. L. Almada, F. Couch, C. Wetmore, M. Pasca di Magliano, M. E. Fernandez-Zapico et al.
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J. S. Khalili, S. Liu, T. G. Rodriguez-Cruz, M. Whittington, S. Wardell, C. Liu, M. Zhang, Z. A. Cooper, D. T. Frederick, Y. Li et al.
Clin. Cancer Res. 18, 5329-5340 (1 October 2012)

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C. Smith, M. Y. Chang, K. H. Parker, D. W. Beury, J. B. DuHadaway, H. E. Flick, J. Boulden, E. Sutanto-Ward, A. P. Soler, L. D. Laury-Kleintop et al.
Cancer Discovery 2, 722-735 (1 August 2012)

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Brain 135, 1055-1069 (1 April 2012)

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Multifaceted link between cancer and inflammation
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Biosci. Rep. 32, 1-15 (1 February 2012)

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H.-C. Cho, C.-Y. Lai, L.-E. Shao, and J. Yu
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X. Jin, J. Yin, S.-H. Kim, Y.-W. Sohn, S. Beck, Y. C. Lim, D.-H. Nam, Y.-J. Choi, and H. Kim
Cancer Res. 71, 7125-7134 (15 November 2011)

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Cancer Res. 71, 5296-5306 (1 August 2011)

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Cancer Res. 68, 9087-9095 (1 November 2008)

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Y.-S. Lee, K.-H. Lim, X. Guo, Y. Kawaguchi, Y. Gao, T. Barrientos, P. Ordentlich, X.-F. Wang, C. M. Counter, T.-P. Yao et al.
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Q. Jia, J. R. Lupton, R. Smith, B. R. Weeks, E. Callaway, L. A. Davidson, W. Kim, Y.-Y. Fan, P. Yang, R. A. Newman et al.
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