NF-κB in Thyroid Cancer: An Update

Abstract

The dysregulated NF-κB basal activity is a common feature of human thyroid carcinomas, especially in poorly differentiated or undifferentiated forms that, even if rare, are often resistant to standard therapies, and, therefore, are uncurable. Despite the molecular mechanisms leading to NF-κB activation in thyroid cancer being only partially understood, during the last few years, it has become clear that NF-κB contributes in different ways to the oncogenic potential of thyroid neoplastic cells. Indeed, it enhances their proliferation and viability, promotes their migration to and colonization of distant organs, and fuels their microenvironment. In addition, NF-κB signaling plays an important role in cancer stem cells from more aggressive thyroid carcinomas. Interfering with the different upstream and/or downstream pathways that drive NF-κB activity in thyroid neoplastic cells is an attractive strategy for the development of novel therapeutic drugs capable of overcoming the therapy resistance of advanced thyroid carcinomas. This review focuses on the recent findings about the key functions of NF-κB in thyroid cancer and discusses the potential implications of targeting NF-κB in advanced thyroid carcinomas.

Keywords: NF-κB; target genes; thyroid cancer.

Figure 1

Thyroid carcinomas and key signaling pathways. Two main cell populations are found in the normal thyroid gland: follicular cells, structurally organized to form thyroid follicles, where they secrete thyroglobulin, and parafollicular C cells, which synthesize, store, and secrete calcitonin. Tumors derived from follicular cells are papillary and follicular carcinomas (PTCs and FTCs, respectively), also defined as differentiated carcinomas (DTCs), that could evolve into poorly differentiated and anaplastic carcinomas (PDTCs and ATCs, respectively). Tumors derived from parafollicular C cells are medullary carcinomas (MTCs). The most important mutated genes involved in thyroid carcinogenesis are indicated.

Figure 2

NF-κB pathways. NF-κB activation occurs through a canonical pathway (on the left), generally triggered by immune and inflammatory stimuli, and a non-canonical/alternative pathway (on the right), mainly induced by genes regulating B lymphocyte survival and secondary lymphoid organ development.

Figure 3

Mechanisms of NF-κB activation in thyroid cancer cells. The constitutive activation of thyroid oncogenes, such as RET/PTC or BRAFV600E, as well the suppression of tumor suppressors, such as PTEN or PPARγ, could trigger NF-κB in aggressive thyroid carcinomas.

Figure 4

NF-κB pathways and main inhibitors. Some of the most common NF-κB inhibitors and their mechanisms of action are indicated.