|Tipo di tesi||Tesi di laurea magistrale|
|Titolo||Validazione dei geni candidati, derivati da una meta-analisi di espressione genica in silico, nella reversione del fenotipo di carcinoma anaplastico della tiroide (ATC)|
|Titolo in inglese||Validation of candidate genes derived from in silico gene expression meta-analysis for reprogramming of anaplastic thyroid carcinoma (ATC) phenotype|
|Struttura||Dipartimento di Scienze della Vita|
|Corso di studi||BIOTECNOLOGIE MEDICHE (D.M. 270/04)|
|Data inizio appello||2020-04-08|
|Disponibilità||Embargo di 3 anni|
|Data di rilascio||2023-04-08|
Il cancro alla tiroide, la neoplasia più comune del sistema endocrino, ha un’incidenza crescente nella popolazione mondiale. Il suo comportamento clinico e la sua prognosi appaiono ampiamente eterogenei a causa del grado di differenziamento delle cellule tumorali.
Thyroid cancer, the most common malignancy of the endocrine system, has shown increasing incidence in the population worldwide. Clinical behavior and prognosis appear widely heterogeneous being affected by the degree of differentiation of tumor cells. Anaplastic Thyroid Carcinoma (ATC) is the less frequent and most aggressive type of thyroid cancer (2-3% of cases). It has a 5-year survival rate of 5% and it contributes to 39% of the total death caused by thyroid cancer. The high mortality rate of ATC is due primarily to the absence of effective therapies being these tumors resistant to classical therapies for thyroid tumor. Due to its rarity and high grade of genetic mutation, ATC is among the most complicated target in thyroid oncology. The epithelial–mesenchymal transition (EMT) is a cellular process by which epithelial cells lose their polarity and adhesions and gain mesenchymal properties such as migration and invasiveness. EMT is essential during normal embryonic development, tissue regeneration and wound healing but it is also involved in tumor progression leading to metastatic expansion, cancer cell “stemness” and resistance to treatments. Starting from publicly available gene expression data, we generated a differential Gene Expression Signature (dGES) comparing Differentiated Thyroid Carcinoma (DTC) to ATC. This dGES was used to interrogate the Connectivity Map (CMap) database, which contains gene signature of cell lines treated with thousands of perturbagenes (FDA-approved drugs, overexpressed and knockdown genes). We obtained a list of genes that when over-expressed or down-regulated, gives gene signatures positively or negatively correlated with dGES (input). Among the top scoring perturbagenes, we found OVOL2 (OVO Like zinc finger 2) whose over-expression induces the GES with the highest inversely correlated score. OVOL2 is a transcription repressor able to suppress EMT and maintain the identity of epithelial cells through the transcriptional repression of several EMT regulators. We validated in vitro the role of OVOL2 in two ATC cell lines, 8505c and Cal-62, by overexpressing it with an inducible lentiviral vector. We demonstrated that OVOL2 induces the inhibition of cell proliferation, adhesion, migration and causes the block of cell cycle in G2/M phase. Overall, our data provide new evidence on the importance of the EMT process in the dedifferentiation and aggressiveness of ATC and offer a clue to a potential therapy target.