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

Kepeng Wang; Min Kyoung Kim; Giuseppe Di Caro; 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

doi:10.1016/j.immuni.2014.11.009

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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aberrant Crypt Foci / genetics
Animals
Antibodies, Blocking / administration & dosage
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Carcinogenesis / drug effects
Carcinogenesis / genetics
Cell Line, Transformed
Colonic Neoplasms / chemically induced
Colonic Neoplasms / drug therapy
Colonic Neoplasms / immunology*
Colorectal Neoplasms / chemically induced
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / immunology*
Disease Models, Animal
Drug Resistance, Neoplasm / drug effects
Enterocytes / drug effects
Enterocytes / physiology*
Extracellular Signal-Regulated MAP Kinases / metabolism
Fluorouracil / administration & dosage
Humans
Interleukin-17 / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
NF-kappa B / metabolism
Receptors, Interleukin-17 / genetics
Receptors, Interleukin-17 / immunology
Receptors, Interleukin-17 / metabolism*
Signal Transduction / drug effects
Signal Transduction / genetics
Tamoxifen / administration & dosage
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Antibodies, Blocking
Il17ra protein, mouse
Interleukin-17
NF-kappa B
Receptors, Interleukin-17
Tamoxifen
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
Fluorouracil

Abstract

Publication types

MeSH terms

Substances

Grants and funding