Interleukin-22 promotes epithelial cell transformation and breast tumorigenesis via MAP3K8 activation

Carcinogenesis. 2014 Jun;35(6):1352-61. doi: 10.1093/carcin/bgu044. Epub 2014 Feb 11.

Abstract

Interleukin-22 (IL-22), one of the cytokines secreted by T-helper 17 (Th17) cells, binds to a class II cytokine receptor containing an IL-22 receptor 1 (IL-22R1) and IL-10R2 and influences a variety of immune reactions. IL-22 has also been shown to modulate cell cycle and proliferation mediators such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but little is known about the underlying molecular mechanisms of IL-22 in tumorigenesis. In this paper, we propose that IL-22 has a crucial role to play in controlling epithelial cell proliferation and tumorigenesis in the breast. IL-22 increased MAP3K8 phosphorylation through IL-22R1, followed by the induction of MEK-ERK, JNK-c-Jun, and STAT3 signaling pathways. Furthermore, IL-22-IL-22R1 signaling pathway activated activator protein-1 and HER2 promoter activity. In addition, Pin1 was identified as a key positive regulator for the phosphorylation-dependent MEK, c-Jun and STAT3 activity induced by IL-22. Pin1(-/-) mouse embryonic fibroblasts (MEF) exhibited significantly a decrease in IL-22-induced MEK1/2, c-Jun, and STAT3 phosphorylation compared with Pin1(+/+) MEF. In addition, a knockdown of Pin1 prevented phosphorylation induced by IL-22. The in vivo chorioallantoic membrane assay also showed that IL-22 increased tumor formation of JB6 Cl41 cells. Moreover, the knockdown of MAP3K8 and Pin1 attenuated tumorigenicity of MCF7 cells. Consistent with these observations, IL-22 levels positively correlate with MAP3K8 and Pin1 expression in human breast cancer. Overall, our findings point to a critical role for the IL-22-induced MAP3K8 signaling pathway in promoting cancer-associated inflammation in the tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Line
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / metabolism*
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterografts
  • Humans
  • Interleukins / metabolism*
  • Interleukins / pharmacology
  • MAP Kinase Kinase Kinases / metabolism*
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-jun / metabolism
  • STAT3 Transcription Factor / metabolism
  • Transcription Factor AP-1 / metabolism

Substances

  • Interleukins
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-jun
  • STAT3 Transcription Factor
  • Transcription Factor AP-1
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP3K8 protein, human
  • PIN1 protein, human
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse
  • interleukin-22