Author of

• 11454

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  P2.01 - Poster Session 2 - Cancer Biology (ID 145)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11455

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    P2.01-001 - Deregulated Interleukin-6 Signaling Suppresses Lung Tumourigenesis in Mice Induced by Nicotine-derived Nitrosamine Ketone (ID 1404)

    09:30 - 09:30  |  Author(s): B. Jenkins
    • Abstract

    Background
    Serum levels of the potent immune-modulatory cytokine interleukin (IL)-6, which signals via the shared gp130 co-receptor, are elevated in smokers, and are higher still in those with lung cancer, the leading cause of cancer death worldwide. However, the precise role that IL-6 plays in the pathogenesis of lung cancer remains to be elucidated. To utilize in vivo molecular dissection of gp130 signaling to identify specific molecular components of the IL-6 cytokine family network which facilitate tobacco-related lung carcinogenesis.

    Methods
    Nicotine-derived Nitrosamine Ketone (NNK) is a potent tobacco carcinogen and reliably induces lung tumours in mice. We therefore examined the effect of deregulated IL-6 signaling on NNK-induced lung carcinogenesis by using gp130[F/F] mice which carry a knock-in mutation in the endogenous gene for gp130, the critical co-receptor for the IL-6 cytokine family.

    Results
    The lungs of these mice display IL-6-induced hyperactivation of the latent transcription factor Stat3 via gp130 in the absence of gp130-mediated PI3K/Akt and Mapk signaling. The gp130[F/F] and control gp130[+/+] (wild-type) mice were injected with NNK or PBS and observed over 16 weeks prior to the evaluation of lung tumourigenesis at the cellular (immunohistochemistry, histology) and molecular (qPCR) levels. In response to NNK, the absolute number of lung lesions in gp130[F/F] mice (3.81 ± 0.84; mean ± SEM) was significantly reduced compared to gp130[+/+ ](6.43 ± 1.72; p<0.05) mice. In addition, we also observed a significant reduction in the size of lesions in gp130[F/F] compared to gp130[+/+] mice (1.00 ± 0.05mm vs 0.69 ± 0.05; p<0.0001). Notably, the number and size of lesions in the lungs of NNK-treated gp130[F/F]:Stat3[-/+] mice displaying genetically-reduced Stat3 hyperactivation were comparable to gp130[F/F] mice.

    Conclusion
    Collectively, our data suggest that IL-6/gp130-mediated activation of the PI3K/Akt and/or Mapk pathways, but not Stat3, plays an important role in promoting NNK-induced lung carcinogenesis.