Wei Tai, Cong Xin, Wang Xiang-Ting, Xu Xiao-Jian, Min Sai-Nan, Ye Peng, Peng Xin, Wu Li-Ling, Yu Guang-Yan
Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, and Beijing Key Laboratory of Digital Stomatology, Beijing, China.
Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
Oncotarget. 2017 Jan 24;8(4):6663-6680. doi: 10.18632/oncotarget.14255.
Interleukin-17A (IL-17A), a proinflammatory cytokine mainly produced by T helper 17 cells, exerts protumor or antitumor effects in different cancer entities. However, the exact role of IL-17A in carcinogenesis and progression of tongue squamous cell carcinoma (TSCC) remains unclear. Here, we found that the levels of IL-17A in serum and tumor samples were significantly increased in TSCC patients and positively correlated with tumor metastasis and clinical stage. Besides, IL-17A enhanced cell migration and invasion in SCC15, a TSCC cell line. Furthermore, IL-17A inversely correlated with miR-23b expression in TSCC specimens. In vitro, NF-κB inhibited miR-23b transcription by directly binding to its promoter region. IL-17A downregulated miR-23b expression via activating NF-κB signaling pathway characterized by increasing p65 expression in the nuclear and elevating the levels of p-IKKα and p-IκBα. Overexpression of miR-23b inhibited, whereas knockdown of miR-23b promoted migration and invasion abilities of SCC15 cells. Moreover, extracellular matrix protein versican was proved to be the direct target of miR-23b through luciferase assay. IL-17A increased versican levels in vitro and knockdown of versican by siRNA inhibited SCC15 cell migration and invasion. Taken together, these results reveal a novel mechanism that IL-17A in TSCC microenvironment promotes the migration and invasion of TSCC cells through targeting miR-23b/versican pathway.
白细胞介素-17A（IL-17A）是一种主要由辅助性T细胞17产生的促炎细胞因子，在不同的癌症实体中发挥促肿瘤或抗肿瘤作用。然而，IL-17A在舌鳞状细胞癌（TSCC）发生和进展中的确切作用仍不清楚。在此，我们发现TSCC患者血清和肿瘤样本中IL-17A水平显著升高，且与肿瘤转移和临床分期呈正相关。此外，IL-17A增强了TSCC细胞系SCC15的细胞迁移和侵袭能力。此外，TSCC标本中IL-17A与miR-23b表达呈负相关。在体外，核因子κB（NF-κB）通过直接结合其启动子区域抑制miR-23b转录。IL-17A通过激活以核内p65表达增加以及p-IKKα和p-IκBα水平升高为特征的NF-κB信号通路下调miR-23b表达。miR-23b过表达抑制SCC15细胞迁移和侵袭能力，而敲低miR-23b则促进其迁移和侵袭能力。此外，通过荧光素酶测定证明细胞外基质蛋白多功能蛋白聚糖是miR-23b的直接靶点。IL-17A在体外增加多功能蛋白聚糖水平，通过小干扰RNA（siRNA）敲低多功能蛋白聚糖可抑制SCC15细胞迁移和侵袭。综上所述，这些结果揭示了一种新机制，即TSCC微环境中的IL-17A通过靶向miR-23b/多功能蛋白聚糖途径促进TSCC细胞的迁移和侵袭。
