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Immunity. 2014 Dec 18;41(6):1052-63. doi: 10.1016/j.immuni.2014.11.009. Epub 2014 Nov 25.

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

Author information

1
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
2
Division of Hematology-Oncology, Department of Medicine, Yeungnam University College of Medicine, 317-1, Daemyung-5 dong, Namgu, Daegu 705-717, South Korea.
3
Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, Guangdong Province, China; Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, 100044 China.
4
Shenzhen Key Laboratory for Translational Medicine of Dermatology, Biomedical Research Institute, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, Guangdong Province, China.
5
Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 1 University Rd, Tainan 70101, Taiwan, ROC.
6
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA; Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
7
Departments of Internal Medicine, Human Genetics and Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
8
Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
9
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA. Electronic address: karinoffice@ucsd.edu.

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 partial contribution 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.

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PMID:
25526314
PMCID:
PMC4272447
DOI:
10.1016/j.immuni.2014.11.009
[Indexed for MEDLINE]
Free PMC Article

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