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
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
Division of Hematology-Oncology, Department of Medicine, Yeungnam University College of Medicine, 317-1, Daemyung-5 dong, Namgu, Daegu 705-717, South Korea.
Immunity. 2014 Dec 18;41(6):1052-63. doi: 10.1016/j.immuni.2014.11.009. Epub 2014 Nov 25.
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.
白细胞介素-17A（IL-17A）是一种促炎细胞因子，与结直肠癌（CRC）的快速恶性进展和治疗耐药性有关。IL-17A通过其A型受体（IL-17RA）发挥其促肿瘤活性。然而，IL-17RA在肿瘤微环境中的许多细胞类型中表达，包括造血细胞、成纤维样细胞和上皮细胞，并且IL-17RA的激活如何促进结肠肿瘤发生尚不清楚。在此，我们表明IL-17RA在转化的结肠上皮细胞（肠上皮细胞）内直接发出信号，以促进早期肿瘤发展。IL-17RA的激活会激活ERK、p38丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）信号通路，并促进刚刚失去APC肿瘤抑制因子表达的致瘤性肠上皮细胞的增殖。虽然IL-17RA信号传导也控制IL-6的产生，但这种机制对结肠肿瘤发生的贡献仅为部分。化疗可诱导IL-17A表达，将化疗与IL-17A中和抗体联合治疗可增强已建立的结肠肿瘤的治疗反应性。这些发现确立了IL-17A和IL-17RA作为结直肠癌的治疗靶点。
