Review
Role of NF-κB in thyroid cancer

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Abstract

Thyroid cancer is the most common neoplasia of the endocrine system and accounts for approximately 1% of all newly diagnosed cancer cases. Its incidence has rapidly grown over the past few decades. Although most thyroid carcinomas are of the well-differentiated papillary histology, and respond well to treatment with surgical resection followed by radioactive iodine ablation, tumors with more aggressive phenotype, such as follicular, poorly differentiated, anaplastic, and medullary cancers, lead to almost 1500 patient deaths annually. Therefore, understanding molecular mechanisms that regulate the biology of these carcinomas could be helpful to identify new molecules acting as novel targets for therapeutic intervention.

NF-κB has been recently shown to play an important role in thyroid cancer for its ability to control the proliferative and the anti-apoptotic signaling pathways of thyroid neoplastic cells. Oncogenic proteins RET/PTC, RAS and BRAF, that are involved in many aspects of thyroid carcinogenesis, can induce NF-κB activation in papillary, follicular, and medullary thyroid carcinomas, while constitutive de-regulated NF-κB activity has been found in anaplastic thyroid carcinomas. A number of NF-κB inhibitors have been demonstrated to induce anti-proliferative effects and/or massive apoptosis, especially in combination with radio- or chemo-therapy. The results obtained suggest that targeting NF-κB could be a promising strategy for advanced thyroid cancer treatment.

Introduction

Thyroid carcinomas mainly comprise four types of tumors: papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), both of which may be summarized as differentiated thyroid carcinoma, medullary thyroid carcinoma (MTC), and undifferentiated anaplastic thyroid carcinoma (ATC). PTC, FTC and ATC derive from the thyroid follicular epithelial cells, while MTC derives from the parafollicular C-cells (Sherman, 2003). PTC is the most common malignant thyroid neoplasm in countries with sufficient iodine diets, and comprises up to 80% of all thyroid malignancies. FTC is more common in regions with insufficient iodine diets and represents approximately 10–20% of all thyroid malignancies (Fagin and Mitsiades, 2008). The overall 5–10-year survival rate of patients with PTC is about 80–95%, while that of patients with FTC is about 70–95% (Gimm, 2001). The incidence of MTC is not well known because epidemiologic studies are rare. Generally, it is believed that MTC comprises about 5–10% of all thyroid malignancies (Gimm, 2001, Sherman, 2003). ATC is one of the most aggressive human malignancies, with a very poor prognosis. Although rare, accounting for up to 1–2% of clinically recognized thyroid cancers, the overall median survival is limited to months (Smallridge et al., 2009). Unfortunately, at the time of diagnosis most of ATC patients already show local and distant metastases, so that surgery, radio-therapy, and chemo-therapy, based primarily on doxorubicin and cisplatin treatment, do not meaningfully improve survival of these patients. Consequently, there is a need for new diagnostic and therapeutic tools for the treatment of these tumors.

An emerging body of literature shows that NF-κB plays a role in thyroid cancer (Visconti et al., 1997, Ludwig et al., 2001, Russell et al., 2003, Vasudevan et al., 2004, Kato et al., 2006, Palona et al., 2006, Gombos et al., 2007, Gallel et al., 2008), especially of anaplastic type (Pacifico et al., 2004, Pacifico et al., 2007, Starenki et al., 2004a, Iannetti et al., 2008, Festa et al., 2009, Zhu et al., 2009). This is an important issue because NF-κB, and particularly the genes under its transcriptional regulation, could potentially become novel molecular targets in ATC therapy, given the ability of NF-κB to control many aspects of thyroid cancer biology. This review will focus on these aspects, in particular on the molecular mechanisms by which NF-κB exerts its role in thyroid tumors.

Section snippets

NF-κB

NF-κB is a family of transcription factors that plays a central role in the regulation of apoptosis, inflammation and immune response (Ghosh et al., 1998, Karin and Ben-Neriah, 2000, Tak and Firestein, 2001). In mammals, the NF-κB family is composed of five members: RelA(p65), RelB, c-Rel, NF-κB1 (p50 and its precursor p100), NF-κB2 (p52 and its precursor p105) (Vallabhapurapu and Karin, 2009). These proteins form homodimers and heterodimers and their activity is regulated by two major

Role of NF-κB in thyroid cancer

Several lines of evidence show that NF-κB plays a role in cancer. Its activity has been found constitutively elevated in many types of human tumors from either haematological or solid origin (Pacifico and Leonardi, 2006). The role of NF-κB in solid tumors has been well documented in several studies performed on primary tumors, and neoplastic cell lines derived from different human tissues. These studies show that the inhibition of constitutive NF-κB activity blocks the oncogenic potential of

NF-κB and apoptosis in thyroid cancer

Cancer cells have the feature to circumvent apoptosis by up-regulating and/or down-regulating a number of genes involved in the control of programmed cell death. This property allows neoplastic cells to survive beyond their normal lifespan, providing protection against hypoxia as tumor mass expands, promoting angiogenesis and invasiveness during tumor progression, and allowing tumor cells to become resistant to radio- and chemo-therapy. Thus, de-regulated apoptosis is a fundamental aspect of

NF-κB links inflammation and cancer

Inflammation is central to control our fight against pathogens, and to regulate wound healing. These are very intricate biological responses that involve complex interactions among different cell types that regulate the expression of biological mediators promoting cell chemotaxis, cell migration, and cell proliferation. If inflammation is not ordered and timely, the resulting chronic inflammation can contribute to a variety of diseases including cancer. Several lines of evidence, based on

NF-κB as therapeutic target in thyroid cancer

While differentiated PTC and FTC have generally a good prognosis after surgery and radio-iodine therapy, poorly differentiated MTC and undifferentiated ATC do not respond to neither radio-iodine treatment, nor conventional chemo- and radio-therapy. These tumors are obvious candidates for alternative therapeutic approaches, such as molecularly targeted therapy. The finding that NF-κB is one of the most important tumor-promoting machinery, prompted the search for drugs able to suppress NF-κB

Conclusions

In the last few years an enormous amount of basic and clinical observations strongly implicate NF-κB in a variety of human tumors, including thyroid cancer. The strongly de-regulated NF-κB activity in human ATC represents a novel finding in the understanding of the molecular biology of thyroid cancer, that joins to those of RET, BRAF, PPARγ, PTEN, whose role has been well established in differentiated thyroid carcinomas. The future challenge is the comprehension of the molecular mechanisms

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