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Abstract
Thyroid cancer has been rapidly increasing in prevalence among humans in last 2 decades and is the most prevalent endocrine malignancy. Overall, thyroid-cancer patients have good rates of long-term survival, but a small percentage present poor outcome. Thyroid cancer aggressiveness is essentially related with thyroid follicular cell loss of differentiation and metastasis. The discovery of oncogenes that drive thyroid cancer (such as RET, RAS, and BRAF), and are aligned in the MAPK/ERK pathway has led to a new perspective of thyroid oncogenesis. The uncovering of additional oncogene-modulated signaling pathways revealed an intricate and active signaling cross-talk. Among these, microRNAs, which are a class of small, noncoding RNAs, expanded this cross-talk by modulating several components of the oncogenic network - thus establishing a new layer of regulation. In this context, TGFβ signaling plays an important role in cancer as a dual factor: it can exert an antimitogenic effect in normal thyroid follicular cells, and promote epithelial-to-mesenchymal transition, cell migration, and invasion in cancer cells. In this review, we explore how microRNAs influence the loss of thyroid differentiation and the increase in aggressiveness of thyroid cancers by regulating the dual function of TGFβ. This review provides directions for future research to encourage the development of new strategies and molecular approaches that can improve the treatment of aggressive thyroid cancer.
Highlights
Thyroid cancer is the most common malignancy of the endocrine system, and its global incidence has increased in recent years; 52 070 new cases are expected to occur in the United States in 2019 [1,2]
BRAF and RAS mutations, and RET/ papillary thyroid cancer (PTC) rearrangements can impair the differentiation of the thyroid follicular cells and lead to PTC oncogenesis due to the constitutive activation of MAPK/ERK signaling [4,5]
These genes are under the regulation of thyroid transcription factors (TFs) such as NKX2-1 (NK2 homeobox 1, previously known as TTF1), FOXE1, and PAX8, which are uniquely co-expressed in the thyroid gland [9]
Summary
Thyroid cancer is the most common malignancy of the endocrine system, and its global incidence has increased in recent years; 52 070 new cases are expected to occur in the United States in 2019 [1,2]. Papillary thyroid cancer (PTC) comprises more than 80% of cases; the remainder consists of follicular thyroid cancer. Less frequent (2%-5% of cases), the undifferentiated thyroid cancer or anaplastic thyroid cancer (ATC) is the most aggressive and lethal type of thyroid cancer [3,4]. The main oncogenic alterations of thyroid cancer occur in genes that are aligned with the MAPK pathway. BRAF and RAS mutations, and RET/ PTC rearrangements can impair the differentiation of the thyroid follicular cells and lead to PTC oncogenesis due to the constitutive activation of MAPK/ERK signaling [4,5]. The oncogenic activation of the MAPK pathway triggers the deregulation of microRNAs (miRNAs), which comprise a class of small noncoding RNAs that exert a potent inhibitory effect on protein expression at the posttranscriptional level. Because miRNAs modulate targets in several oncogenic pathways [7], they expand the network of oncogene-modulated genes in thyroid cells’ functioning and biology
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