Interleukin-17 induces AP-1 activity and cellular transformation via upregulation of tumor progression locus 2 activity

Carcinogenesis. 2013 Feb;34(2):341-50. doi: 10.1093/carcin/bgs342. Epub 2012 Nov 3.

Abstract

Inflammatory conditions elicited by extrinsic environmental factors promote malignant transformation, tumor growth and metastasis. Although the role of T cells in cancer promotion has been examined, little is known about the underlying molecular mechanisms of interleukin-17 A (IL-17A), a proinflammatory cytokine produced by activated CD4(+) memory T cells, in carcinogenesis. Here, we report that IL-17A induces neoplastic transformation of JB6 Cl41 cells through activation of tumor progression locus 2 (TPL2). IL-17A dose- and time-dependently increases TPL2 phosphorylation in JB6 Cl41 cells through IL-17A receptor. IL-17A activates mitogen-activated protein kinase/extracellular signal-regulated kinase kinases, c-jun N-terminal kinases and STAT3 signaling pathways, which are inhibited by a TPL2 kinase inhibitor (TKI). Furthermore, IL-17A activates c-fos and c-jun promoter activity, resulting in increased activator protein-1 (AP-1) activity. When small interfering RNA of IL-17A receptor (IL-17R), IL-17A and TPL2 were introduced into JB6 Cl41 cells, respectively, IL-17A-induced AP-1 activity was significantly decreased compared with control cells. Similarly, TPL2 inhibition suppressed AP-1 activity induced by IL-17A. The knockdown of IL-17R and TKI treatment in JB6 Cl41 cells resulted in decreased IL-17A-induced cell transformation. The in vivo chorioallantoic membrane assay also showed that IL-17A increased tumor formation of JB6 Cl41 cells, whereas TKI inhibited the tumorigenesis promoted by IL-17A. Consistent with these observations, knockdown of IL-17A and/or inhibition of TPL2 attenuated tumorigenicity of human breast cancer MCF7 cells. Together, our findings point to a critical role for the IL-17A-induced TPL2 signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may, therefore, effectively inhibit carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / drug therapy
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / pathology
  • Cell Adhesion
  • Cell Proliferation
  • Cell Transformation, Neoplastic / drug effects*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Chickens
  • Chorioallantoic Membrane
  • Epidermal Cells
  • Epidermis / drug effects
  • Epidermis / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Immunoenzyme Techniques
  • Interleukin-17 / pharmacology*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA, Small Interfering / genetics
  • Receptors, Interleukin-17 / metabolism
  • Signal Transduction
  • Transcription Factor AP-1 / metabolism*
  • Transcriptional Activation

Substances

  • Interleukin-17
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • RNA, Small Interfering
  • Receptors, Interleukin-17
  • Transcription Factor AP-1
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP3K8 protein, human