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

Abstract

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. .

Overexpression of lncRNA SLC26A4‐AS1 inhibits papillary thyroid carcinoma progression through recruiting ETS1 to promote ITPR1‐mediated autophagy

“…In lung cancer, ETS1 contributes to transactivation of Twist1, a gene involved in tumour cell motility and dissemination, thereby worsening the condition 31 . It is also indicated as a member of thyroid tumour‐oncogenic driver dysregulation in PTC, 32 but the role is not clarified clearly. The interaction between ETS1 and lncRNA was previously noted in lung cancer 33 .…”

The PDZ protein SCRIB regulates sodium/iodide symporter (NIS) expression at the basolateral plasma membrane

“…Site-directed mutagenesis was performed by PCR with oligonucleotides carrying the desired mutation using KOD Hot Start DNA polymerase (EMD Millipore), which was followed by template plasmid digestion with DpnI (New England Biolabs). 9 All constructs were sequenced to verify specific nucleotide substitutions (Macrogen -Seoul, South Korea).…”

“…The expression vectors encoding GFP‐tagged Rab4a, Rab5, Rab14, Lamp1, and CD63 were kindly provided by Dr José Echenique and Dr Gustavo Chiabrando (Universidad Nacional de Córdoba, Argentina). Site‐directed mutagenesis was performed by PCR with oligonucleotides carrying the desired mutation using KOD Hot Start DNA polymerase (EMD Millipore), which was followed by template plasmid digestion with DpnI (New England Biolabs) 9 . All constructs were sequenced to verify specific nucleotide substitutions (Macrogen – Seoul, South Korea).…”

LncRNA AFAP-AS1 promotes anaplastic thyroid cancer progression by sponging miR-155-5p through ETS1/ERK pathway

“…EST1 is a well-known tumorigenic transcription factor which regulates the cytokine and chemokine genes in a wide variety of different physiological and pathological activity directly [ 21 ]. It has been reported that ETS1 not only influence mitogen-activated protein kinase1 (ERK) expression but also its phosphorylation [ 22 , 23 ]. ERK, extracellular signal-regulated kinase, affects cell growth by controlling many proteins through its kinase activity or transcription factor function.…”