Interleukin-17 Receptor A Signaling in Transformed Enterocytes Promotes Early Colorectal Tumorigenesis

Title
Interleukin-17 Receptor A Signaling in Transformed Enterocytes Promotes Early Colorectal Tumorigenesis
Author(s)
김민경Karin M[Karin M]Wang K[Wang K]Di Caro G[Di Caro G]Shalapour S[Shalapour S]Wang J[Wang J]Zhang W[Zhang W]Zhong Z[Zhong Z]Sanchez-Lopez E[Sanchez-Lopez E]Wu LW[Wu LW]Taniguchi K[Taniguchi K]Feng Y[Feng Y]Fearon E[Fearon E]Grivennikov SI[Grivennikov SI]
Keywords
COLITIS-ASSOCIATED CANCER; INTESTINAL EPITHELIAL-CELLS; T-CELLS; SUPPRESSOR-CELLS; APC INACTIVATION; GASTRIC-CANCER; TUMOR-GROWTH; COLON-CANCER; MOUSE MODEL; IFN-GAMMA
Issue Date
201412
Publisher
CELL PRESS
Citation
IMMUNITY, v.41, no.6, pp.1052 - 1063
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, fibro-blastoid, 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-kappa B 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.
URI
http://hdl.handle.net/YU.REPOSITORY/30322http://dx.doi.org/10.1016/j.immuni.2014.11.009
ISSN
1074-7613
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의과대학 > 내과학교실 > Articles
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