TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells

Abstract

The sodium-iodide symporter (NIS) mediates transport of iodide across the basolateral membrane of thyroid cells. NIS expression in thyroid cancer (TC) cells allows the use of radioactive iodine (RAI) as a diagnostic and therapeutic tool, being RAI therapy the systemic treatment of choice for metastatic disease. Still, a significant proportion of patients with advanced TC lose the ability to respond to RAI therapy and no effective alternative therapies are available. Defective NIS expression is the main reason for impaired iodide uptake in TC and NIS downregulation has been associated with several pathways linked to malignant transformation. NF-κB signaling is one of the pathways associated with TC. Interestingly, NIS expression can be negatively regulated by TNF-α, a bona fide activator of NF-κB with a central role in thyroid autoimmunity. This prompted us to clarify NF-kB's role in this process. We confirmed that TNF-α leads to downregulation of TSH-induced NIS expression in non-neoplastic thyroid follicular cell-derived models. Notably, a similar effect was observed when NF-κB activation was triggered independently of ligand-receptor specificity, using phorbol-myristate-acetate (PMA). TNF-α and PMA downregulation of NIS expression was reverted when NF-κB-dependent transcription was blocked, demonstrating the requirement for NF-kB activity. Additionally, TNF-α and PMA were shown to have a negative impact on TSH-induced iodide uptake, consistent with the observed transcriptional downregulation of NIS. Our data support the involvement of NF-κB-directed transcription in the modulation of NIS expression, where up-or down-regulation of NIS depends on the combined output to NF-κB of several converging pathways. A better understanding of the mechanisms underlying NIS expression in the context of normal thyroid physiology may guide the development of pharmacological strategies to increase the efficiency of iodide uptake. Such strategies would be extremely useful in improving the response to RAI therapy in refractory-TC.

Salvianolic acid B inhibits RAW264.7 cell polarization towards the M1 phenotype by inhibiting NF-κB and Akt/mTOR pathway activation

“…Then, the mRNA expression of iNOS was increased and that of Arg-1 was decreased in the PMA group compared with the Sal B group. PMA has been shown to induce canonical NF-κB-dependent transcription by acting through the direct activation of protein-kinase-C 56 , 57 . Moreover, the ELISA results indicated that the TNF-α and IL-6 levels were increased, and the IL-10 level was decreased.…”

Evaluating the Natrium Iodide Symporter Expressions in Thyroid Tumors

“…Higher NIS expression is associated with higher uptake of 131 I by thyroid cell [18], [34]. Thyroid cells that do not respond to radioiodine can be lost NIS expression [15], [17], [23], [24]. The availability of specific polyclonal and monoclonal anti-hNIS antibodies has allowed the investigation of NIS protein expression levels in various thyroid tissues.…”

“…On the other hand, some thyroid cancers and metastases showed low uptake of 131 I compare to healthy thyroid tissues [16]. One-third of advanced DTC metastases show low avidity to iodine [8], [17], [18], [19]. Losing the ability to concentrate iodine can occur during the progression of the disease.…”

“…Decreased NIS expression levels or diminished NIS targeting to thyroid cancer cells' plasma membrane lead to radioiodine-refractory disease. The main reason for impaired of 131 I uptake is defective of NIS expression [15], [17], [23], [24]. This study aims to analyze the NIS expression in thyroid tumors.…”

Transplantable human thyroid organoids generated from embryonic stem cells to rescue hypothyroidism

“…Second, we added dexamethasone (from day 30) and the TGFb inhibitor SB431542 (from day 37), based on transcriptomic data showing substantial levels of TGFb pathway markers (Extended data Fig. 2f) among NKX2-1 cells, and the known inhibition of thyroid differentiation by inflammation and TGFb pathway stimulation [27][28][29][30][31] .…”