The Role of the Transcription Factor Nuclear Factor-kappa B in Thyroid Autoimmunity and Cancer

Abstract

Nuclear factor-kappa B (NF-κB) is a ubiquitous transcription factor that is involved in inflammatory and immune responses, as well as in regulation of expression of many other genes related to cell survival, proliferation, and differentiation. In mammals, NF-κB comprises five subunits that can bind to promoter regions of target genes as homodimers or heterodimers. The most common dimer is the p50/p65 heterodimer. The several combinations of dimers that can be formed contribute to the heterogeneous regulation of NF-κB target genes, and this heterogeneity is further increased by interactions of the NF-κB dimers with other transcription factors, such as steroid hormone receptors, activator protein-1 (AP-1), and cAMP response element binding protein (CREB). In the thyroid, several studies have demonstrated the involvement of NF-κB in thyroid autoimmunity, thyroid cancer, and thyroid-specific gene regulation. The role of NF-κB in thyroid autoimmunity was hypothesized more than 20 years ago, after the finding that the binding of distinct NF-κB heterodimers to the major histocompatibility complex class I gene is hormonally regulated. Further studies have shown increased activity of NF-κB in thyroid autoimmune diseases and in thyroid orbitopathy. Increased activity of NF-κB has also been observed in thyroid cancer, where it correlates with a more aggressive pattern. Of particular interest, mutation of some oncogenes or tumor suppressor genes involved in thyroid carcinogenesis results in constitutive activation of the NF-κB pathway. More recently, it has been shown that NF-κB also has a role in thyroid physiology, as it is fundamental for the expression of the main thyroid-specific genes, such as sodium iodide symporter, thyroid peroxidase, thyroglobulin, Pax8, and TTF-1 (NKX2-1).

Integrative Analysis of Methylation and Transcriptome Identified Epigenetically Regulated lncRNAs With Prognostic Relevance for Thyroid Cancer

“…For example, mast cell infiltrates are linked to extrathyroidal extension and invasiveness (Visciano et al, 2015). NF-κB is associated with inflammatory and immune responses and its increased activity correlate with a more aggressive phenotype of THCA (Giuliani et al, 2018). Finally, we validated the functional roles of one selected methylation-driven lncRNA signature by in situ hybridization analysis in 119 PTC tissues and paired with adjacent normal tissues.…”

Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?

“…More recently, Takeda et al [ 105 ] proposed that DMF prolongs survival in melanoma mouse models and exerts its anti-metastatic efficacy through suppression of nuclear translocation of NF-κB. NF-κB is constitutively active in several types of cancer [ 107 , 108 , 109 ]. Especially in breast cancer, NF-κB signalling enhances tumour cell survival, migration, invasion, angiogenesis and resistance to anti-cancer therapy [ 110 , 111 ].…”

Dexamethasone Inhibits Spheroid Formation of Thyroid Cancer Cells Exposed to Simulated Microgravity

“…NF-κB transcription factors play a fundamental role in the tumorigenesis of many cancer types, including thyroid cancer [41,42] and may be a target in the treatment of advanced thyroid cancer [43]. DEX is known to have inhibitory effects on the NF-κB pathway [44].…”