UNCOVERING SOLUBLE AGONISTS TRIGGERING TOLL-LIKE RECEPTOR 4 SIGNALING IN THYROID CARCINOMAS

Buenos Aires

Congreso; XVII Latin American Thyroid Congress; 2019

Sociedad Latinoamericana de Tiroides

Introduction: Although increased NF-κB activity is associated with a pro-inflammatory microenvironment in aggressive thyroid cancer,the mechanism underlying NF-κB activation remains unclear. Recently, we evidenced that Toll-like receptor 4 (TLR4) stimulationtrigger NF-κB signaling in thyroid cancer. Objectives: To investigate thyroid cancer-secreted endogenous TLR4 agonists able totrigger NF-κB signaling. Methods: Experiments were performed on PCCl3 cells, PCCl3 cells conditionally expressing BRAFV600E(PC/BRAFV600E), and BRAFV600E-mutant 8505c thyroid cancer cells. Gene reporter assays were used to evaluate NF-κB transcriptionalactivity. Transcriptomic analysis were based on multiple public access datasets deposited on The Cancer Genome Atlas and GeneExpression Omnibus. Results: Conditioned media (CM) from PC/BRAFV600E stimulate NF-κB transcriptional activity in PCCl3cells carrying an NF-κB reporter. This effect is TLR4-dependent as pre-incubation of PCCl3 cells with the TLR4 signaling inhibitorTAK-242 abrogate NF-κB transcriptional activity. CM from 8505c cells stimulate NF-κB signaling in PCCl3 cells. Pre-incubation of8505c cells with the BRAFV600E inhibitor PLX4032 abrogate CM-stimulated NF-κB signaling in PCCl3 cells. Transcriptomic analysisrevealed a significant upregulation of endogenous TLR4 agonists (Fibronectin-1, Tenascin-C) in papillary and anaplastic carcinomas.No significant modulation of known endogenous TLR4 agonists was evidenced in follicular carcinomas. Conclusion: EndogenousTLR4 agonists secreted to the tumor microenvironment may stimulate TLR4-dependent NF-κB transcriptional activity, thus promotinga pro-inflammatory environment associated with thyroid cancer progression