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| Author(s): |
Paola Marino Dantônio
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) |
| Defense date: | 2019-12-04 |
| Examining board members: |
Edna Teruko Kimura;
Carolina Beltrame Del Debbio;
Gisele Giannocco;
Joao Roberto Maciel Martins
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| Advisor: | Edna Teruko Kimura |
| Abstract | |
Thyroid cancer is an endocrine neoplasia with increasing incidence over the last years. More than 80% of cases consist of papillary carcinomas (PTC), which are usually well differentiated and present good prognosis. However, a fraction of patients is diagnosed with aggressive disease and bad prognosis. These cases are frequently resistant to conventional therapy and present low-grade cell differentiation, being considered poorly differentiated or anaplastic (ATC). The loss of differentiation is characterized by the loss of expression of thyroid differentiation markers such as thyroglobulin (Tg), thyroperoxidase (TPO), sodium/iodine symporter (NIS), among others. The acquisition of stem cell features by cancer cells has been reported in several cancers, and reactivation of embryonic signaling pathways is one of the possible mechanisms involved in this process. The Nodal signaling pathway is crucial for mesoderm induction and anterior-posterior axis formation during embryogenesis. Nodal is a ligand belonging to TGF-ß superfamily, which has members with deregulated expression in thyroid tumors, such as TGF-ß 1 and activins A and B. Reactivation of Nodal signaling has been reported in cancer and associated with more aggressive phenotypes. We show through immunohistochemistry staining that NODAL is present in follicular cells of PTC, but not ATC. NODAL overexpression in PTC cell line decreases cell proliferation but does not affect sphere formation capacity or the expression of pluripotency and thyroid differentiation genes, while NODAL knock down increases expression of SOX2 and NIS. Both NODAL overexpression and knock down do not influence the activation of Smad signaling. We also identified microRNAs with reduced expression in PTC samples and potentially involved in the regulation of Nodal pathway, besides discussing the challenges of measuring Nodal protein and mRNA expression. Our results show that, contrary to what is observed in other types of cancer, NODAL is expressed in well differentiated thyroid carcinomas rather than in ATC. Moreover, NODAL overexpression does not promote stem cell-like phenotype in differentiated thyroid cancer cell line. Together, our data suggest that NODAL loss might be associated with less differentiated phenotypes in thyroid cancer, as evidenced by our immunohistochemistry results. Thus, further experiments such as NODAL overexpression should be conducted with ATC cell lines. Furthermore, the use of more advanced models such as animal and 3D culture could be employed to study the involvement of tumor microenvironment, once cell line model is limited and do not recapitulate the tumor heterogeneity found in câncer in vivo. (AU) | |
| FAPESP's process: | 17/04639-7 - Influence of Notch/Nodal signalling pathways cross-talk and microRNAs in thyroid cancer |
| Grantee: | Paola Marino Dantonio |
| Support Opportunities: | Scholarships in Brazil - Master |