Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis.
Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis.
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DOI：
10.1016/j.immuni.2014.11.009
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发表时间：
2014-12-18
期刊：
影响因子：
32.4
通讯作者：
Karin, Michael
中科院分区：
文献类型：
--
作者：
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
白细胞介素-17A（IL-17 A）是与结直肠癌（CRC）的快速恶性进展和治疗抗性相关的促炎细胞因子。IL-17 A通过其A型受体（IL-17 RA）发挥其促肿瘤发生活性。然而，IL-17 RA参与如何促进结肠肿瘤发生尚不清楚，因为IL-17 RA在肿瘤微环境中的许多细胞类型中表达，包括造血细胞、成纤维细胞和上皮细胞。在这里，我们表明，IL-17 RA信号直接转化结肠上皮细胞（肠上皮细胞），以促进早期肿瘤的发展。IL-17 RA参与激活ERK、p38 MAPK和NF-κB信号传导，并促进刚刚失去APC肿瘤抑制因子表达的致瘤肠细胞的增殖。虽然IL-17 RA信号传导也控制IL-6的产生，但这种机制仅对结肠肿瘤发生做出部分贡献。与诱导IL-17 A表达的化疗和IL-17 A中和抗体的联合治疗增强了已建立的结肠肿瘤的治疗反应性。这些发现确立了IL-17 A和IL-17 RA作为结直肠癌的治疗靶点。
Interleukin-17A (IL-17A) is a proinflammatory 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, how IL-17RA engagement promotes colonic tumorigenesis is unknown, as IL-17RA is expressed in many cell types in the tumor microenvironment, including hematopoietic, fibroblastoid and epithelial cells. 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 who just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls 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.
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影响因子：
29.4
作者：
Feng Y;Bommer GT;Zhao J;Green M;Sands E;Zhai Y;Brown K;Burberry A;Cho KR;Fearon ER
通讯作者：
Fearon ER
影响因子：
4.7
作者：
Hyun, Yil Sik;Han, Dong Soo;Kim, Ho-Youn
通讯作者：
Kim, Ho-Youn
影响因子：
3.7
作者：
He D;Li H;Yusuf N;Elmets CA;Athar M;Katiyar SK;Xu H
通讯作者：
Xu H
影响因子：
64.8
作者：
Grivennikov, Sergei I.;Wang, Kepeng;Mucida, Daniel;Stewart, C. Andrew;Schnabl, Bernd;Jauch, Dominik;Taniguchi, Koji;Yu, Guann-Yi;Oesterreicher, Christoph H.;Hung, Kenneth E.;Datz, Christian;Feng, Ying;Fearon, Eric R.;Oukka, Mohamed;Tessarollo, Lino;Coppola, Vincenzo;Yarovinsky, Felix;Cheroutre, Hilde;Eckmann, Lars;Trinchieri, Giorgio;Karin, Michael
通讯作者：
Karin, Michael
影响因子：
5.8
作者：
Alshaker HA;Matalka KZ
通讯作者：
Matalka KZ