Interplay of TGFβ signaling and microRNA in thyroid cell loss of differentiation and cancer progression

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.

MicroRNAs miR-146-5p and let-7f as prognostic tools for aggressive papillary thyroid carcinoma: a case report / MicroRNAs miR-146-5p e let-7f como ferramenta de prognóstico para o carcinoma papilífero de tiroide: relato de caso

Papillary thyroid cancer (PTC) is the most incident histotype of thyroid cancer. A certain fraction of PTC cases (5%) are irresponsive to conventional treatment, and refractory to radioiodine therapy. The current prognostic factors for aggressiveness are mainly based on tumor size, the presence of lymph node metastasis, extrathyroidal invasion and, more recently, the presence of the BRAFT1799A mutation. MicroRNAs (miRNAs) have been described as promising molecular markers for cancer as their deregulation is observed in a wide range of tumors. Recent studies indicate that the over-expression of miR-146b-5p is associated with aggressiveness and BRAFT1799A mutation. Furthermore, down-regulation of let-7f is observed in several types of tumors, including PTC. In this study, we evaluated the miR146b-5p and let-7f status in a young male patient with aggressive, BRAFT1799A-positive papillary thyroid carcinoma, with extensive lymph node metastases and short-time recurrence. The analysis of miR-146b-5p and let-7f expression revealed a distinct pattern from a cohort of PTC patients, suggesting caution in evaluating miRNA expression data as molecular markers of PTC diagnosis and prognosis. Arq Bras Endocrinol Metab. 2012;56(8):552-7.

O carcinoma papilífero (PTC) é o histotipo mais prevalente de câncer de tiroide. Cerca de 5% dos casos são refratários ao tratamento convencional e à radioiodoterapia. Os fatores prognósticos para agressividade mais utilizados atualmente são o tamanho do tumor, a presença de metástases linfonodais ao diagnóstico, a presença de invasão extratiroideana e, mais recentemente, a presença da mutação BRAFT1799A. A análise de perfil de expressão de microRNAs (miRNA) mostra que esses pequenos RNAs são marcadores moleculares promissores para o câncer, por apresentarem desregulação de sua expressão em uma ampla gama de tumores, includindo o PTC. Estudos recentes revelam a associação entre o aumento da expressão do miRNA e miR-146b-5p e a presença da mutação BRAFT1799A como um fator de pior prognóstico no PTC. Além disso, observa-se a diminuição da expressão de let-7f em diversos tipos de tumores, incluindo tumores tiroideanos. Neste relato de caso, realizamos a quantificação da expressão de miR-146b-5p e let-7f em um paciente jovem, de sexo masculino, apresentando PTC positivo para a mutação BRAFT1799A com extensas metástases linfonodais ao diagnóstico e recidiva precoce. A análise da expressão de miR-146b-5p e let-7f mostrou um padrão diferente do observado em um grupo de pacientes PTC, sugerindo a necessidade de cautela na interpretação da expressão de miRNAs como marcador molecular no diagnóstico e prognóstico de PTC. Arq Bras Endocrinol Metab. 2012;56(8):552-7.