Promotion of lung tumor growth by interleukin-17

Beibei Xu, James F. Guenther, Derek A. Pociask, Y. Wang, Gilbert F. Morris, You Zongbing, Bysani Chandrasekar, Bin Shan, Deborah E. Sullivan

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Abstract

Recent findings demonstrate that inhaled cigarette smoke, the predominant lung carcinogen, elicits a T helper 17 (Th17) inflammatory phenotype. Interleukin-17A (IL-17), the hallmark cytokine of Th17 inflammation, displays pro- and anti-tumorigenic properties in a manner that varies according to tumor type and assay system. To investigate the role of IL-17 in lung tumor growth, we used an autochthonous tumor model (K-RasLA1 mice) with lung delivery of a recombinant adenovirus that expresses IL-17A. Virus-mediated expression of IL-17A in K-RasLA1 mice at 8–10 wk of age doubled lung tumor growth in 3 wk relative to littermates that received a green fluorescent protein-expressing control adenovirus. IL-17 induced matrix metalloproteinase-9 (MMP-9) expression in vivo and in vitro. In accord with this finding, selective and specific inhibitors of MMP-9 repressed the increased motility and invasive-ness of IL-17-treated lung tumor cells in culture. Knockdown or mutation of p53 promoted the motility of murine lung tumor cells and abrogated the promigratory role of IL-17. Coexpression of siRNA-resistant wild-type, but not mutant, human p53 rescued both IL-17-mediated migration and MMP-9 mRNA induction in p53 knockdown lung tumor cells. IL-17 increased MMP-9 mRNA stability by reducing interaction with the mRNA destabilizing serine/arginine-rich splicing factor 1 (SRSF1). Taken together, our results indicate that IL-17 stimulates lung tumor growth and regulates MMP-9 mRNA levels in a p53- and SRSF1-dependent manner.

Original languageEnglish (US)
Pages (from-to)L497-L508
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume307
Issue number6
DOIs
StatePublished - Sep 15 2014

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Keywords

  • IL-17
  • Lung tumor growth
  • MMP-9
  • SRSF1
  • p53

Cite this

Xu, B., Guenther, J. F., Pociask, D. A., Wang, Y., Morris, G. F., Zongbing, Y., Chandrasekar, B., Shan, B., & Sullivan, D. E. (2014). Promotion of lung tumor growth by interleukin-17. American Journal of Physiology - Lung Cellular and Molecular Physiology, 307(6), L497-L508. https://doi.org/10.1152/ajplung.00125.2014