Interleukin-6 mediated inflammasome activation promotes oral squamous cell carcinoma progression via JAK2/STAT3/Sox4/NLRP3 signaling pathway

J Exp Clin Cancer Res. 2022 May 5;41(1):166. doi: 10.1186/s13046-022-02376-4.

Abstract

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.

Keywords: IL-6; JAK2; NLRP3 inflammasome; NLRP3 pathway; Oral squamous cell carcinoma; STAT3; Sox4.

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell* / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Head and Neck Neoplasms*
  • Humans
  • Inflammasomes / metabolism
  • Interleukin-6 / metabolism
  • Janus Kinase 2
  • Mice
  • Mouth Neoplasms* / pathology
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • SOXC Transcription Factors / genetics
  • SOXC Transcription Factors / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Squamous Cell Carcinoma of Head and Neck

Substances

  • Inflammasomes
  • Interleukin-6
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • SOX4 protein, human
  • SOXC Transcription Factors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • JAK2 protein, human
  • Janus Kinase 2