Locally Targeting the IL-17/IL-17RA Axis Reduced Tumor Growth in a Murine B16F10 Melanoma Model
Locally Targeting the IL-17/IL-17RA Axis Reduced Tumor Growth in a Murine B16F10 Melanoma Model
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DOI：
10.1089/hum.2018.104
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发表时间：
2018-10-03
影响因子：
4.2
通讯作者：
Shen, Chia-Rui
中科院分区：
文献类型：
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作者：
Chen, Ya-Shan;Huang, Tse-Hung;Shen, Chia-Rui
白细胞介素(IL)-17和在肿瘤微环境中产生它的细胞似乎可以促进肿瘤的发展，并与癌症患者的生存有关。在这里，我们研究了IL-17/IL-17受体A （IL-17RA）轴在调节黑色素瘤进展中的作用，并评估了阻断IL-17/IL-17RA通路的治疗潜力。首先，重组小鼠IL-17 （mIL-17）处理显著增加小鼠B16F10细胞和人A375和A2058细胞的增殖。在B16F10细胞中，通过小发夹RNA （shRNA）沉默IL-17RA可减少mil -17诱导的细胞增殖、迁移和侵袭，并显著减少血管内皮生长因子和基质金属蛋白酶的产生。值得注意的是，IL-17RA的敲低导致B16F10细胞在体内形成肿瘤的能力显著下降，与il -17缺陷小鼠相似。最后，局部应用一种腺病毒，传递针对IL-17RA mRNA的shRNA，不仅可以显著抑制肿瘤的发展，还可以通过增加表达干扰素的T细胞而不是T调节细胞来增强抗肿瘤免疫。我们的研究结果强调了IL-17/IL-17RA通路在肿瘤进展中的关键作用，并暗示靶向IL-17RA是一种很有前景的治疗策略。
Interleukin (IL)-17 and the cells that produce it within the tumor microenvironment appear to promote tumor development and are associated with survival in cancer patients. Here we investigated the role of the IL-17/IL-17 receptor A (IL-17RA) axis in regulating melanoma progression and evaluated the therapeutic potential of blocking the IL-17/IL-17RA pathway. First, recombinant mouse IL-17 (mIL-17) treatment significantly increased proliferation of mouse B16F10 cells and human A375 and A2058 cells. Silencing IL-17RA by small hairpin RNA (shRNA) in B16F10 cells reduced the mIL-17-elicited cell proliferation, migration, and invasion, and significantly reduced vascular endothelial growth factor and matrix metalloproteinase production. Remarkably, knockdown of IL-17RA led to a significantly decreased capability of B16F10 cells to form tumors in vivo, similar to that in IL-17-deficient mice. Finally, local application of an adenovirus delivering a shRNA against IL-17RA mRNA not only significantly suppressed tumor development, but also enhanced antitumor immunity by increasing the interferon -expressing T cells and not T regulatory cells. Our results highlight the critical role of the IL-17/IL-17RA pathway in tumor progression and imply that targeting IL-17RA represents a promising therapeutic strategy.