Ricerc@Sapienza

Thyroid cancer (TC) is a frequent neoplasm in the endocrine system. Altered expression of miRNAs has been observed during TC evolution and progression. In particular, increased miR-221 and 222 expression has prognostic value in differentiated TC (DTC) and has been initially associated with deregulation of the cell cycle. Subsequently, in DTC cells, increase in miR-221 and 222 has been associated with the presence of extracellular HMGB1, a nuclear protein that is released by necrotic or stressed cells. Interestingly, cytosolic and extracellular accumulation of HMGB1 is favored by acetylation of lysines in the nuclear localization sequence (NLS). Moreover, deacetylation of these lysines is controlled by the nuclear NAD-dependent deacetylase SIRT1, member of the sirtuins family. Another interesting aspect is that SIRT1 is a target of miR-221 and 222 in chronic inflammation or prostate cancer. Based on these evidences, our hypothesis is that the presented aspects may be mechanistically connected forming, in DTC, a loop favoring cancer cells growth and invasion. For this reason our project aims to connect these separate aspects in a unifying mechanism consisting in a vicious loop in which increased miR-221 and 222 decrease SIRT1 expression that, in turn, increases acetylation of HMGB1. Acetylated HMGB1 accumulates into the cytosol where induces protective autophagy and in the extracellular space where it favors miR-221 and 222 increase in adjacent cells. Moreover, we also aim to treat DTC spheroids with functionalized graphene oxide nanoparticles combined with anti-miR-221 and 222, SIRT1 activators, HMGB1 or autophagy inhibitors in order to reach inner cancer cells to prevent or inhibit such loop.
In conclusion, our study will define a new molecular loop for DTC development and provide a strategy to limit such a mechanism and, finally, DTC growth and progression.