TY - JOUR
T1 - Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis
AU - Wang, Kepeng
AU - Kim, Min Kyoung
AU - DiCaro, Giuseppe
AU - Wong, Jerry
AU - Shalapour, Shabnam
AU - Wan, Jun
AU - Zhang, Wei
AU - Zhong, Zhenyu
AU - Sanchez-Lopez, Elsa
AU - Wu, Li Wha
AU - Taniguchi, Koji
AU - Feng, Ying
AU - Fearon, Eric
AU - Grivennikov, Sergei I.
AU - Karin, Michael
N1 - Funding Information:
We thank Dr. Shujuan Chen for scientific discussion; eBioscience, GeneTex, Santa Cruz, and Cell Signaling for antibodies; Amgen and Dr. Sylvie Robine for Il17ra −/− and Villin Cre-ERT2 mice, respectively. This work was supported by the Croucher Foundation and China Postdoctoral Science Foundation (20110490919) to K.W.; Italian Association for Cancer Research, AIRC Fellowship for Abroad to G.D.C.; Canadian Institutes of Health Research Postdoctoral Fellowship to J. Wong; German Research Foundation Fellowship to S.S.; Shenzhen Science and Technology Project (GJHZ20120616153140827) to J.W.; Cancer Research Institute Irvington Postdoctoral Fellowship to Z.Z.; traveling grant NSC-101-2918-I-006-005 by the National Science Council in Taiwan to L.W.W.; Postdoctoral Fellowship for Research Abroad, the Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science, and the Uehara Memorial Foundation Fellowship to K.T.; NIH/NIDDK R00DK088589, FCCC-Temple University Nodal grant, AACR-Landon Innovator Award in Tumor Microenvironment, and the Pew Scholar in Biomedical Sciences Program to S.I.G.; and NIH (AI043477; DK035108) and American Association for Cancer Research (07-60-21-KARI) grants to M.K., who is an American Cancer Society Research Professor and the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/12/18
Y1 - 2014/12/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84918535539&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84918535539&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2014.11.009
DO - 10.1016/j.immuni.2014.11.009
M3 - Article
C2 - 25526314
AN - SCOPUS:84918535539
SN - 1074-7613
VL - 41
SP - 1052
EP - 1063
JO - Immunity
JF - Immunity
IS - 6
ER -