Thyroid cancer is the most common endocrine cancer with predominant prevalence of papillary thyroid cancer (PTC) histotype, that frequently presents with epithelial-mesenchimal transition through which cells express mesenchymal markers associated with metastases and aggressive behavior. This process, called epithelial to mesenchymal transition (EMT) is characterized by the loss of epithelial markers and the acquisition of mesenchymal ones such as vimetin, desmin and others. Genetic and epigenetic alterations originated in the tumor stroma are responsible of these changes. Hypoxic conditions and many molecules such as HMGB1, HGF, EGF, PDGF and TGF beta have been identified as inducers of the EMT process in thyroid cancer. MiRNAs play an important role in thyroid cancer and the overexpression of miR221, 222 and many others is associated with tumor progression.
One way through which cells communicate and transfer information to one another in solid tumors or between tumor and microenvironment is through the release of vesicles (EV) that contain proteins and nucleic acids able to deliver both inhibitory and stimulating messages. Small non coding RNAs that are known regulators of protein expression, found in microvesicles, are implicated in most cell processes from survival, proliferation and acquisition of stem cell markers. The opposite process i.e mesenchymal-epithelial transition (MET) in which mesenchymal cells are converted into epithelial cells is still poorly understood, and much more work needs to be done to gain a firm grasp of how it works. This project aims to study the mechanisms that may induce EMT in papillary tumor cell lines (BC PAP) and the reverse transition (MET) from stemness to differentiation in thyroid cancer cell lines. Among the EMT promoters miR 9, 200 a and 200c have been shown to play a role in thyroid cancer progression while inhibitory microRNAs such as miR599 and 520a repress EMT by down regulation of activating signaling pathways.
Based on etiology, morphology, and clinical behaviour, thyroid cancers are divided in well differentiated thyroid cancers (DTCs), poorly differentiated thyroid cancers (PDTCs), anaplastic thyroid cancers (ATCs), and medullary thyroid cancers (MTCs). DTCs account for 90% of all thyroid cancers and have relatively good prognosis. These tumors maintain the typical differentiation characteristics of thyroid tissue such as the ability to capture iodine, synthesize thyroglobulin, and respond to TSH (thyroid stimulating hormone). These phenotypic properties are lost by cancer cells passing from well differentiated to poorly differentiated carcinomas up to anaplastic carcinomas, which are the most undifferentiated. About 80-85% of patients show a good response to traditional therapies that include surgery, radioiodine treatment and TSH suppressive therapy. The remaining 15-20% of patients experiences recurrence or persistence of disease, often associated with resistance to radioiodine treatment. Findings from our and other reseach groups have underlined the importance of thyroid cancer microenvironment in the prognosis and treatment of this malignancy (12) . Our reasearch would add more information on the modalities that make DTCs acquire stemness markers (EMT) that lead to invasion, recurrence and metastasis. This could help the development of new strategies in cancer immunotherapy that could represent an alternative treatment for those tumors that are not responsive to conventional therapies such as recurrent or persistent DTC, PTc, DTC, or ATC. The molecular mechanisms that regulate EMT and MET are poorly understood. Especially in thyroid gland little is known about the role of cancer stem cells and their relationship with the microenvironment. Further, multiple miRNA families regulate the expression of a single EMT transcription factor; likewise a single miRNA controls several EMT components. miRNAs that positively regulate cancer EMT are: miR-9, miR-10b, miR-21, miR-29a, miR-31, miR-155 and miR-490-3p (13). However some miRNAs that have been found to be under-expressed during the EMT thyroid tumor process, could be implied in the repression of growth, invasion and metastases. miR 599, for example promotes apoptosis and represses proliferation and EMT of papillary thyroid carcinoma cells via down regulation of NOTCH signaling pathway. Furthermore miR 520a interferes with the JAK/STAT signaling pathway (14). Our research will focus on miRs that are able to induce down-regulation of activatory pathways and will add knowledge that could be used for programming new therapeutic approaches. Up-regulation of miR 599 and miR 520a have recently been shown to inhibit growth of papillary tumor cells (15-16). We will study if miR 599 and miR 520 are released in EVs from differentiated cells and if their oncosuppressor function can be transferred to anaplastic cells.
12. Greening DW, Gopal SK, Mathias RA, et al. Semin Cell Dev Biol. 2015 doi:10.1016/j.semcdb.2015.02.008.
13. Garnier D, Magnus N, Lee TH, et al. J Biol Chem. 2012; 287:43565-7.
14. Zaravinos A. J Oncol. 2015;2015:865.
15. Wang DP et al. J Cell Physiol. 2020
16. Bi CL et al. J Cell Physiol. 2019;234:4054-4067.