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

Wang, Kepeng; Kim, Min Kyoung; Di Caro, Giuseppe; Wong, Jerry; Shalapour, Shabnam; Wan, Jun; Zhang, Wei; Zhong, Zhenyu; Sanchez-Lopez, Elsa; Wu, Li-Wha; Taniguchi, Koji; Feng, Ying; Fearon, Eric; Grivennikov, Sergei I; Karin, Michael.
Immunity; 41(6): 1052-63, 2014 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-25526314
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.
Selo DaSilva