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Thyroid carcinomas are the most common endocrine tumors in humans, with a globally increasing incidence. Differentiated tumors, such as papillary (PTC) and follicular (FTC) thyroid cancers, are often curable with surgical resection and radiotherapy, whereas undifferentiated (anaplastic) thyroid carcinoma (ATC) is invariably lethal, due to the high invasiveness and insensitivity to radioiodine or chemotherapeutic treatment. Little is known about the molecular events that lead from the highly curable differentiated tumors to the very aggressive ATC. Through, a cDNA microarray analysis on different thyroid tumors we have isolated Twist1 as a gene upregulated in ATC. Twist1 is a highly conserved basic helix-loop-helix transcription factor that plays an important role in the development and progression of human cancer. Twist1 has been associated with epithelial-tomesenchymal transition (EMT) a key step during embryonic morphogenesis and in the progression of primary tumors toward metastasis. In this dissertation, we have shown that approximately 50% of ATCs upregulate Twist1 with respect to normal thyroids as well as to poorly- and well-differentiated thyroid carcinomas. Knockdown of Twist1 by RNA interference in ATC cells reduced cell migration and invasion and increased sensitivity to apoptosis. The ectopic expression of Twist1 in thyroid cells induced resistance to apoptosis and increased cell migration and invasion. To understand the molecular mechanisms through which Twist1 exert is biological effects in thyroid cancer cells, we have performed a microarray analysis of thyroid cancer cells ectopically expressing Twist1 in comparison to vector control cells. We have identified a set of 20 genes involved in migration, invasion and apoptosis; expression levels of these genes changed upon Twist1 overexpression or knockdown. Silencing of 5 of the 20 target genes reduced viability of thyroid cancer cells overexpressing Twist1. Thus, our data suggest that Twist1 plays a key role in determining malignant features of the anaplastic phenotype and identifies a set of Twist1 target genes that could be used as molecular target for the therapy of ATC.

10 páginas, 5 figuras, 1 tabla.-- et al., [Context]:Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human tumors; it is characterized by chemoresistance, local invasion, and distant metastases. ATC is invariably fatal. [Objective]:The aim was to study the role of TWIST1, a basic helix-loop-helix transcription factor, in ATC. [Design]:Expression of TWIST1 was studied by immunohistochemistry and real-time PCR in normal thyroids and well-differentiated, poorly differentiated, and ATC. The function of TWIST1 was studied by RNA interference in ATC cells and by ectopic expression in well-differentiated thyroid carcinoma cells. [Results]:ATCs up-regulate TWIST1 with respect to normal thyroids as well as to poorly and well-differentiated thyroid carcinomas. Knockdown of TWIST1 by RNA interference in ATC cells reduced cell migration and invasion and increased sensitivity to apoptosis. The ectopic expression of TWIST1 in thyroid cells induced resistance to apoptosis and increased cell migration and invasion. [Conclusions]:TWIST1 plays a key role in determining malignant features of the anaplastic phenotype in vitro., This work was supported by the Associazione Italiana per la Ricerca sul Cancro, the Istituto Superiore di Oncologia, the Italian Ministero della Salute, the Ministero dell’Università e della Ricerca, the European Community Contract FP6-36495, and the Programa Ramón y Cajal–Ministerio de Ciencia e Innovación, Social EU Funds, Universidad de Valladolid, Spain.