Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal
Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal
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激活的 STING 通过 c-jun/CCL22 信号增强舌鳞状细胞 HPV 相关癌变过程中 Tregs 的浸润
DOI：
10.1016/j.bbadis.2015.08.011
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发表时间：
2015-11-01
影响因子：
6.2
通讯作者：
Hou, Ya-Yi
中科院分区：
文献类型：
--
作者：
Ding, Liang;Huang, Xiao-Feng;Hou, Ya-Yi
IFN基因激活刺激因子（STING）在自身炎症性疾病和癌症中的负面作用已经被发现。然而，STING在病毒相关致癌作用中的作用尚不清楚。本文中，随机收集HPV+舌鳞状细胞癌（TSCC）（n = 25）和HPV-TSCC（n = 25）样品，并通过原位杂交（ISH）和p16免疫组织化学（IHC）验证，以通过IHC评估STING的表达和活化状态。结果显示，STING的表达在TSCC的发展过程中上调。有趣的是，尽管STING的表达在HPV+/- TSCC样品之间没有显示出差异，但在HPV+ TSCC样品中观察到STING的激活状态，其在核周围呈深染色。通过SiRNA在三种细胞系中分析了激活的STING的作用，表明激活的STING对细胞活力或细胞凋亡没有影响，但促进了几种免疫抑制细胞因子的诱导，例如，IL-10、IDO和CCL 22，其促进调节性T细胞（TcB）的浸润。此外，在HPV+ TSCC样品中证实了Foxp 3（+）TSCC浸润的增加以及CCL 22表达的增加沿着。MAPK/AP-1通路的抑制剂（U 0126）和c-jun的沉默显著抑制了CCL 22诱导和通过活化STING募集Tcl 3。此外，在独立的新鲜TSCC样品（n = 50）和8个细胞系中验证了下调的miR-27，这增强了STING激活并导致TSCC微环境中TSTING募集的CCL 22表达增加。因此，我们的发现提供了对激活的STING在HPV相关致癌作用中的副作用的独特见解。(C)2015 Elsevier B. V.版权所有。
The negative role of the activated stimulator of IFN genes (STING) has been uncovered in autoinflammatory disease and cancer. However, the role of STING in virus-related carcinogenesis is not well known. Herein, HPV+ tongue squamous cell carcinoma (TSCC) (n = 25) and HPV- TSCC samples (n = 25) were randomly collected and were verified by in situ hybridization (ISH) and p16 immunohistochemistry (IHC) to assess the expression and activated status of STING through IHC. The results showed that the expression of STING was up-regulated during the development of TSCC Interestingly, although the expression of STING showed no difference between HPV+/- TSCC samples, the activated status of STING with dark staining around the nucleus was observed in HPV+ TSCC samples. The role of activated STING was analyzed in three cell lines by siRNA and indicated that activated STING had no impact on cell viability or apoptosis but promoted the induction of several immunosuppressive cytokines, e.g., IL-10, IDO and CCL22, which facilitated the infiltration of regulatory T cells (Tregs). Moreover, increased infiltration of Foxp3(+) Tregs along with increased expression of CCL22 was confirmed in HPV+ TSCC samples. An inhibitor of the MAPK/AP-1 pathway (U0126) and the silencing of c-jun significantly suppressed CCL22 induction and the recruitment of Tregs by activated STING. Furthermore, down-regulated miR-27 was verified in independent fresh TSCC samples (n = 50) and eight cell lines, which enhanced STING activation and led to increased CCL22 expression for Tregs recruitment in the TSCC microenvironment Therefore, our findings provided distinct insight into the side effects of activated STING in HPV-related carcinogenesis. (C) 2015 Elsevier B.V. All rights reserved.