Medullary thyroid cancer (MTC) is a tumor marked by an indolent growth for which few prognostic factors and therapeutic strategies are actually available. Different studies have recently appraised well-differentiated thyroid cancers are characterized by a dysregulation in different microRNA sets; however, only few of them investigated the role of miRNA expression in MTCs. In this study, we have assessed the miR-375 expression in a series of 130 MTCs (104 are sporadic and 26 familial) with a median follow-up of 39 months (range 1–138) and then we have correlated our results with the clinical–pathological features and the patients’ outcome.

Moreover, we have appraised YAP1 (Yes-associated protein 1) immunohistochemical expression in the same MTC series and in 5 C-cells hyperplasia (CCH) samples as well. We observed a significant upregulation of miR-375 in all MTCs, when compared to the normal thyroid tissues. Besides, miR-375 expression was found to be closely linked to neoplastic size, a chance of thyroid capsule infiltration, the risk of lymph node metastasis, and the staging of the tumor. At the end of follow-up, only 10% (13/130) showed a tumor progression and a higher miR-375 expression was found to be closely linked to a worst patient’ outcome. On the contrary, YAP1 immunohistochemical expression was sharply downregulated in tumors, whereas it was weakly expressed in CCHs. Our results suggest miR-375 plays a central role in MTC progression and, therefore, we seek following the idea that miR-375 pathway may be an effective target in novel MTC therapeutic strategies.