The epithelial-mesenchymal transition (EMT) is a reversible cellular program that allows the phenotypic transition of epithelial cells to mesenchymal ones. EMT is essential to the formation of many tissues and organs during development, but it has also been shown to occur in wound healing, in organ fibrosis and the initiation of metastasis for cancer progression. Accumulating evidence points to a critical role of EMT-like events during tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. Gene expression patterns identified in human cancers indicate that de-differentiated cancer cells combine EMT properties with a stem-cell like phenotype through the expression of specific transcription factors, including the
Snail family, Twist and Zeb, which can co-induce EMT and stemness properties. Some studies evidenced the expression of EMT biomarkers in both differentiated and undifferentiated thyroid carcinomas, and EMT was shown to induce generation of cancer stem cells (CSCs) and tumor progression in human thyroid cancer cells in vitro. On this basis, the present research proposal is aimed to investigate the expression levels of the zinc finger transcriptional repressors Snail1 and Snail2, the basic helix-loop-helix transcription factors Twist1, and the zinc finger transcription factors Zeb-1 and Zeb-2 in differentiated thyroid carcinomas and their normal matched tissues. In presence of gene expression alterations, the expression level of the above genes will be correlated with patient¿s clinico-pathological parameters and disease recurrences to establish their possible prognostic value.
Differentiated thyroid cancers derived from the epithelial follicular thyroid cell represent the most common endocrine malignancy accounting for roughly 1% of all new malignant diseases and about 0.4% of deaths related to cancer. Compared to other malignancies, the prognosis of thyroid carcinomas is favorable, with the 10 years survival rate of patients affected by PTC of about 90%. However,about 20-30% of patients face the morbidity of disease recurrences and PTC-related deaths. The most widely used staging system for thyroid cancer patients is represented by the TNM (Turnar size, lymph Node and distant Metastasis) system developed by the American Joint Committee on Cancer and the lnternational Union Against Cancer (2009 AJCC cancer staging manual. 7th ed. New York:Springer-Verlag 2009).This staging system is strongly influenced by the patient¿s age, with those above 45 yr receiving a worse prognosis despite other factors being equa l. The TNM, as well as other staging systems proposed by recognized international organizations, are capable of making a rough prediction of the high or low risk of cancer mortality leaving, however, in the same risk group patients showing different disease-specific progression and survival time. Similarly, they fail to predict the risk of cancer recurrences. Regarding the latter, both the European (ETA) and the American Thyroid Associations (ATA) proposed practical guidelines in which the TNM parameters are integrated by additional clinical factors, such as tumor histological variant and the results of post-ablative whole body scan and the serum Tg levels. Despite that, patients included in the same risk group still show a very heterogeneous behavior in terms of disease-free interval. In addition, the stratification risk proposed by the ATA and the ETA is not accurate in predicting the long-term outcome in PTC patients, having a very low positive predictive value. Therefore, the identification of new prognostic molecular biomarkers able to testify tumor aggressiveness and improve the prognosis of PTC patients is highly required. In the present research project, by evaluating the expression of genes closely involved in the epithelial-mesenchymal transition, we seek to expand our knowledge on the molecular pathogenesis of thyroid cancer progression, and we also point to the identification and characterization of one or more genes capable of improving the prognosis of thyroid cancer patients.