Journal
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume 41, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13046-022-02376-4
Keywords
IL-6; Oral squamous cell carcinoma; NLRP3 inflammasome; JAK2; STAT3; Sox4; NLRP3 pathway
Categories
Funding
- National Natural Science Foundation of China [81502362]
- Science and Technology Foundation of Chengdu, China [2021-YF05-00442-SN]
- Doctoral Foundation of Sichuan Provincial People's Hospital, China [30305030574]
- Science and Technology Foundation of Sichuan Province, China [2017JY0082]
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This study confirmed that IL-6 plays an oncogenic role in the progression of OSCC by activating the JAK2/STAT3/Sox4/NLRP3 pathway, which may be a therapeutic target for OSCC remedy.
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.
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