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Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis.

Abstract
Interleukin (IL)-21 triggers inflammatory signals that contribute to the growth of neoplastic cells in mouse models of colitis-associated colorectal cancer (CRC). Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man. IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN-γ-expressing T-bet/RORγt double-positive CD3+CD8- cells. Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival. In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells. IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apc(min/+) mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size. IL-21 deficiency was associated with reduced STAT3/NF-kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-α and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apc(min/+) mice. Altogether, data suggest that IL-21 promotes a protumorigenic inflammatory circuit that ultimately sustains the development of sporadic CRC.
AuthorsVeronica De Simone, Giulia Ronchetti, Eleonora Franzè, Alfredo Colantoni, Angela Ortenzi, Massimo C Fantini, Angelamaria Rizzo, Giuseppe S Sica, Pierpaolo Sileri, Piero Rossi, Thomas T MacDonald, Francesco Pallone, Giovanni Monteleone, Carmine Stolfi
JournalOncotarget (Oncotarget) Vol. 6 Issue 12 Pg. 9908-23 (Apr 30 2015) ISSN: 1949-2553 [Electronic] United States
PMID25839161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Interferon-alpha
  • Interleukins
  • NF-kappa B
  • STAT3 Transcription Factor
  • interleukin-21
Topics
  • Animals
  • Carcinogenesis
  • Cell Growth Processes (immunology)
  • Cell Transformation, Neoplastic (immunology, pathology)
  • Colonic Neoplasms (immunology, pathology)
  • Female
  • HT29 Cells
  • Humans
  • Inflammation (immunology, pathology)
  • Interferon-alpha (immunology)
  • Interleukins (biosynthesis, immunology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B (immunology)
  • STAT3 Transcription Factor (biosynthesis, immunology)
  • Signal Transduction

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