title: Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis.
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.
authors.affiliation: 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.
authors.forename: Kepeng
authors.initials: K
authors.lastname: Wang
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Yeungnam University College of Medicine, 317-1, Daemyung-5 dong, Namgu, Daegu 705-717, South Korea.
authors.forename: Min Kyoung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Caro
authors.affiliation: 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.
authors.forename: Jerry
authors.initials: J
authors.lastname: Wong
authors.affiliation: 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.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Shalapour
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: 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.
authors.forename: Elsa
authors.initials: E
authors.lastname: Sanchez-Lopez
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 1 University Rd, Tainan 70101, Taiwan, ROC.
authors.forename: Li-Wha
authors.initials: LW
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Departments of Internal Medicine, Human Genetics and Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Departments of Internal Medicine, Human Genetics and Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Fearon
authors.affiliation: Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Grivennikov
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D058739:Aberrant Crypt Foci / Q000235:genetics; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020895:Enterocytes / Q000187:drug effects / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D016328:NF-kappa B; D053722:Receptors, Interleukin-17; D013629:Tamoxifen; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005472:Fluorouracil