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 - 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.
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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 -