白细胞介素-6 介导的炎症小体激活通过 JAK2/STAT3/Sox4/NLRP3 信号通路促进口腔鳞状细胞癌的进展。
Interleukin-6 mediated inflammasome activation promotes oral squamous cell carcinoma progression via JAK2/STAT3/Sox4/NLRP3 signaling pathway.
机构信息
Department of Stomatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China.
出版信息
J Exp Clin Cancer Res. 2022 May 5;41(1):166. doi: 10.1186/s13046-022-02376-4.
BACKGROUND
Interleukin-6 (IL-6) has been reported to be critical in oral squamous cell carcinoma (OSCC). However, the set of pathways that IL-6 might activate in OSCC are not fully understood.
METHODS
IL-6 and Sox4 expressions were first determined with RT-qPCR, ELISA, Western blot, or immunohistochemistry in OSCC tissues, and correlations between IL-6 and Sox4 expression and patient pathological characteristics were examined, and Kaplan-Meier approach was employed for evaluating the prognostic utility in OSCC patients. CCK-8, EdU stain and colony formation assays were utilized to test cell proliferation in vitro. Mechanistically, downstream regulatory proteins of IL-6 were verified through chromatin immunoprecipitation, luciferase reporter, pull-down, and the rescued experiments. Western blot was used for detecting protein expression. A nude mouse tumorigenicity assay was used to confirm the role of IL-6 and Sox4 in vivo.
RESULTS
IL-6 was upregulated in OSCC tissues, and Sox4 expression was positively correlated with IL-6 expression. High IL-6 and Sox4 expression was closely related to tumor size, TNM stage, and a poorer overall survival. Besides, IL-6 could accelerate OSCC cell proliferation by activating inflammasome via JAK2/STAT3/Sox4/NLRP3 pathways in vitro and in vivo. Furthermore, STAT3 played as a transcription factor which positively regulated Sox4, and IL-6 promotes Sox4 expression by activating JAK2/STAT3 pathway. Moreover, through the rescue experiments, we further confirmed that IL-6 could promote proliferation and NLRP3 inflammasome activation via JAK2/STAT3/Sox4 pathway in OSCC cells. Finally, knockdown of Sox4 suppressed OSCC growth in vivo, and antagonized the acceleration of IL-6 on tumor growth.
CONCLUSIONS
We confirmed that IL-6 plays an oncogenic role in OSCC progression by activating JAK2/STAT3/Sox4/NLRP3 pathway, which might be the therapeutic targets for OSCC remedy.
背景
白细胞介素 6（IL-6）已被报道在口腔鳞状细胞癌（OSCC）中起关键作用。然而，IL-6 可能在 OSCC 中激活的途径尚不完全清楚。
方法
首先通过 RT-qPCR、ELISA、Western blot 或免疫组织化学法在 OSCC 组织中确定 IL-6 和 Sox4 的表达，检测 IL-6 和 Sox4 表达与患者病理特征之间的相关性，并采用 Kaplan-Meier 方法评估 OSCC 患者的预后。体外通过 CCK-8、EdU 染色和集落形成实验检测细胞增殖。通过染色质免疫沉淀、荧光素酶报告、下拉和挽救实验验证 IL-6 的下游调节蛋白。通过 Western blot 检测蛋白表达。通过裸鼠肿瘤生成实验验证 IL-6 和 Sox4 在体内的作用。
结果
IL-6 在 OSCC 组织中上调，Sox4 表达与 IL-6 表达呈正相关。高 IL-6 和 Sox4 表达与肿瘤大小、TNM 分期和总体生存率较差密切相关。此外，IL-6 通过 JAK2/STAT3/Sox4/NLRP3 途径在体外和体内加速 OSCC 细胞增殖。此外，STAT3 作为转录因子，正向调节 Sox4，IL-6 通过激活 JAK2/STAT3 通路促进 Sox4 表达。此外，通过挽救实验，我们进一步证实，IL-6 可以通过 JAK2/STAT3/Sox4 通路促进 OSCC 细胞的增殖和 NLRP3 炎性小体激活。最后，敲低 Sox4 抑制体内 OSCC 生长，并拮抗 IL-6 对肿瘤生长的加速作用。
结论
我们证实，IL-6 通过激活 JAK2/STAT3/Sox4/NLRP3 通路在 OSCC 进展中发挥致癌作用，这可能是 OSCC 治疗的靶点。
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