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

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.

Profiling and Cellular Analyses of Obesity-Related circRNAs in Neurons and Glia under Obesity-like In Vitro Conditions

“…We analyzed the protein-coding potential of candidate circRNAs to confirm the possibility of protein translation ( Figure 6 A). The protein-coding potential of seven circRNAs was confirmed using two prediction tools: CPC 2.0 and CPAT [ 38 , 39 ]. It was confirmed that some circRNAs, except circSnx12 and circUsp3, are highly likely to code proteins.…”

“…We used the coding potential calculator 2 (CPC 2.0, accessed on 25 January 2023) and the coding potential assessment tool (CPAT, accessed on 25 January 2023) for the prediction of coding potential for the selected circRNAs [ 38 , 39 ]. To predict circRNA-interacting proteins, we performed the analysis as previously described [ 31 ].…”

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells

“…In particular, the Nod-like receptor protein 3 (NLRP3) inflammasome can be primed or indirectly activated by inflammatory cytokines (e.g. IL-1β, IL-6) that are often found as components of the SASP (38,(54)(55)(56).…”

The Multiple Roles of CD147 in the Development and Progression of Oral Squamous Cell Carcinoma: An Overview

“…Such a rise in MMP levels accelerates and enlarges the degradation of interstitial and peritumoral matrices, creating new space for the proliferation and invasion of cancer cells and thereby augmenting the size of the tumor mass ( Figure 2 ). It should also be considered that the inflammatory cytokines and growth factors whose synthesis is promoted by CD147 can directly promote OSCC proliferation [ 140 , 199 , 200 , 201 ]. Moreover, the survival and growth of OSCC cells are sustained by the activation of AKT and MAPK, which follows CD147 triggering ( Figure 1 and Figure 2 ) [ 61 , 62 , 63 , 64 , 65 ].…”