IL-17A/IL-17RA promotes invasion and activates MMP-2 and MMP-9 expression via p38 MAPK signaling pathway in non-small cell lung cancer
IL-17A/IL-17RA promotes invasion and activates MMP-2 and MMP-9 expression via p38 MAPK signaling pathway in non-small cell lung cancer
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IL-17A/IL-17RA通过p38 MAPK信号通路促进非小细胞肺癌侵袭并激活MMP-2和MMP-9表达
DOI：
10.1007/s11010-018-3483-9
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发表时间：
2019-05-01
影响因子：
4.3
通讯作者：
Wang, Hongjiang
中科院分区：
文献类型：
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作者：
Wu, Zhenhua;He, Dan;Wang, Hongjiang
本研究旨在探究白细胞介素（IL）-17A及其受体IL-17RA对非小细胞肺癌（NSCLC）的作用及作用机制。研究共纳入139例非小细胞肺癌患者，收集患者的非小细胞肺癌组织及癌旁组织。选用人非小细胞肺癌细胞系H157、H1975和A549进行体外研究。采用MTT法检测细胞增殖情况；采用划痕愈合实验检测细胞迁移能力；采用Transwell实验检测细胞的迁移和侵袭能力。通过实时荧光定量聚合酶链反应检测mRNA表达水平，采用蛋白质免疫印迹法检测蛋白表达水平。运用免疫组织化学法评估139例原发性人非小细胞肺癌组织中IL-17RA的表达情况。结果显示，非小细胞肺癌组织中IL-17RA水平高于癌旁正常组织，且与临床结局相关。Kaplan-Meier生存分析表明，IL-17RA表达阳性的非小细胞肺癌患者生存率较低。此外，IL-17A/IL-17RA在体外影响非小细胞肺癌细胞的迁移和侵袭。IL-17A/IL-17RA处理可增加非小细胞肺癌细胞中基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）的表达。再者，在IL-17RA过表达的非小细胞肺癌细胞中，p38的磷酸化增强。p38丝裂原活化蛋白激酶（p38 MAPK）特异性抑制剂SB203580可抑制非小细胞肺癌细胞的迁移和侵袭。MMP-2和MMP-9是IL-17RA和p38信号通路的下游效应分子。本研究表明，p38 MAPK的活性对IL-17A/IL-17RA促进非小细胞肺癌转移至关重要。此外，IL-17A/IL-17RA信号通路可能是治疗非小细胞肺癌的一个新的、有前景的癌症治疗靶点。
The present study is to investigate the effect and mechanism of action of interleukin (IL)-17A and its receptor IL-17RA on non-small cell lung cancer (NSCLC). A total of 139 NSCLC patients were included in the study. NSCLC tissues and tumor-adjacent tissues were collected from the patients. Human NSCLC cell lines H157, H1975, and A549 were used for in vitro studies. MTT assay was performed to determine cell proliferation. Wound healing assay was used to determine cell motility. Transwell assay was carried out to detect migration and invasion. Quantitative real-time polymerase chain reaction was conducted to measure mRNA expression, while Western blotting was used for determine protein expression. Immunohistochemistry was employed to evaluate IL-17RA expression in 139 primary human NSCLC tissues. Levels of IL-17RA in NSCLC tissues were higher than tumor-adjacent normal tissues, and associated with clinical outcomes. Kaplan–Meier survival analysis indicated that NSCLC patients with positive IL-17RA expression had a poor survival. In addition, IL-17A/IL-17RA affected NSCLC cell migration and invasion in vitro. Treatment with IL-17A/IL-17RA increased the expression of MMP-2 and MMP-9 in NSCLC cells. Furthermore, phosphorylation of p38 was enhanced in IL-17RA-overexpressing NSCLC cells. P38 MAPK-specific inhibitor SB203580 suppressed the migration and invasion of NSCLC cells. MMP-2 and MMP-9 were downstream effectors of IL-17RA and p38 signaling pathways. The present study demonstrates that P38 MAPK activity is crucial for IL-17A/IL-17RA to promote NSCLC metastasis. In addition, IL-17A/IL-17RA signaling may be a novel and promising cancer therapeutic target for the treatment of NSCLC.