Functional Toll-like Receptor 4 Overexpression in Papillary Thyroid Cancer by MAPK/ERK-Induced ETS1 Transcriptional Activity

• Published in: Molecular cancer research 2018-05, Vol.16 (5), p.833-845
• Main Authors: Peyret, Victoria, Nazar, Magalí, Martín, Mariano, Quintar, Amado A, Fernandez, Elmer A, Geysels, Romina C, Fuziwara, Cesar S, Montesinos, María M, Maldonado, Cristina A, Santisteban, Pilar, Kimura, Edna T, Pellizas, Claudia G, Nicola, Juan P, Masini-Repiso, Ana M
• Format: Article
• Language: English
• Subjects: Activation; Binding sites; Cancer; Correlation analysis; Data analysis; Data processing; Ets-1 protein; Extracellular signal-regulated kinase; Gene expression; Genomes; Immune system; Lipopolysaccharides; Lymph nodes; MAP kinase; Metastases; NF-κB protein; Papillary thyroid cancer; Papillary thyroid carcinoma; Proteins; Signaling; Survival; Thyroid; Thyroid gland; TLR4 protein; Toll-like receptors; Transcription; Tumorigenesis; Tumors
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-17-0433

Emerging evidence suggests that unregulated Toll-like receptor (TLR) signaling promotes tumor survival signals, thus favoring tumor progression. Here, the mechanism underlying TLR4 overexpression in papillary thyroid carcinomas (PTC) mainly harboring the BRAF mutation was studied. TLR4 was overexpressed in PTC compared with nonneoplastic thyroid tissue. Moreover, paired clinical specimens of primary PTC and its lymph node metastasis showed a significant upregulation of TLR4 levels in the metastatic tissues. In agreement, conditional BRAF expression in normal rat thyroid cells and mouse thyroid tissue upregulated TLR4 expression levels. Furthermore, functional TLR4 expression was demonstrated in PTC cells by increased NF-κB transcriptional activity in response to the exogenous TLR4-agonist lipopolysaccharide. Of note, The Cancer Genome Atlas data analysis revealed that BRAF -positive tumors with high TLR4 expression were associated with shorter disease-free survival. Transcriptomic data analysis indicated a positive correlation between TLR4 expression levels and MAPK/ERK signaling activation. Consistently, chemical blockade of MAPK/ERK signaling abrogated BRAF -induced TLR4 expression. A detailed study of the promoter revealed a critical MAPK/ERK-sensitive Ets-binding site involved in BRAF responsiveness. Subsequent investigation revealed that the Ets-binding factor ETS1 is critical for BRAF -induced MAPK/ERK signaling-dependent gene expression. Together, these data indicate that functional TLR4 overexpression in PTCs is a consequence of thyroid tumor-oncogenic driver dysregulation of MAPK/ERK/ETS1 signaling. Considering the participation of aberrant NF-κB signaling activation in the promotion of thyroid tumor growth and the association of high TLR4 expression with more aggressive tumors, this study suggests a prooncogenic potential of TLR4 downstream signaling in thyroid tumorigenesis. .