Pathophysiological and translational implications of the dysregulation of molecular machineries controlling RNA metabolism in thyrotropinomas.

The contribution of post-transcriptional regulation remains largely unexplored in thyrotropin-secreting pituitary tumors (TSHomas), a rare endocrine pathology responsible for inappropriate TSH secretion and central hyperthyroidism. We investigated the TSHoma post-transcriptional regulatory landscape by analyzing components of molecular machineries controlling RNA metabolism [spliceosome/RNA-exosome/nonsense-mediated decay (NMD)], their associations with clinical parameters, and the impact of their pharmacological inhibition in TSHoma cells. A drastic dysregulation of multiple components of spliceosome [spliceosome (SF3B2/U2AF35/PRPF40A) and splicing factors (e.g., SRP30C/EIF4A3/DDX1/TRA2B/HNR NN F…)], RNA-Exosome (e.g., DIS3/DIS3L/PABPN1), and NMD [e.g., PABPC1, and NMD-canonical targets (DDIT3/GADD45B/MAFF/PDRG1/ATF4/ATF3)] was found in TSHomas vs. non-tumor pituitaries with some of these alterations associated with relevant clinical features (e.g., tumor size, TSHB/fT4-levels). Moreover, we demonstrate a clear antiproliferative action of spliceosome/RNA-Exosome/NMD inhibitors in primary patient-derived TSHoma cells. Overall, a clinically relevant spliceosome/RNA-Exosome/NMD-associated molecular dysregulation and antiproliferative actions of these machineries' inhibition are demonstrated in TSHomas, highlighting a potential source of novel diagnostic/prognostic biomarkers and therapeutic tools in TSHomas.