Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis

Kepeng Wang, Min Kyoung Kim, Giuseppe DiCaro, Jerry Wong, Shabnam Shalapour, Jun Wan, Wei Zhang, Zhenyu Zhong, Elsa Sanchez-Lopez, Li Wha Wu, Koji Taniguchi, Ying Feng, Eric Fearon, Sergei I. Grivennikov, Michael Karin

Research output: Contribution to journalArticlepeer-review

187 Citations (Scopus)

Abstract

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine linked to rapid malignant progression of colorectal cancer (CRC) and therapy resistance. IL-17A exerts its pro-tumorigenic activity through its type A receptor (IL-17RA). However, IL-17RA is expressed in many cell types, including hematopoietic, fibroblastoid, and epithelial cells, in the tumor microenvironment, and how IL-17RA engagement promotes colonic tumorigenesis is unknown. Here we show that IL-17RA signals directly within transformed colonic epithelial cells (enterocytes) to promote early tumor development. IL-17RA engagement activates ERK, p38 MAPK, and NF-κB signaling and promotes the proliferation of tumorigenic enterocytes that just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls the production of IL-6, this mechanism makes only a partialcontribution to colonic tumorigenesis. Combined treatment with chemotherapy, which induces IL-17A expression, and an IL-17A neutralizing antibody enhanced the therapeutic responsiveness of established colon tumors. These findings establish IL-17A and IL-17RA as therapeutic targets in colorectal cancer.

Original languageEnglish
Pages (from-to)1052-1063
Number of pages12
JournalImmunity
Volume41
Issue number6
DOIs
Publication statusPublished - 2014 Dec 18
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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