Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

摘要: Aberrant thyroid hormone receptors (TRs) are found in over 70% of the human hepatocellular carcinomas (HCCs) analysed. To better understand role(s) these TR mutants this neoplasia, we analysed a panel HCC mutant for their molecular properties. Virtually all HCC-associated tested retained ability to repress target genes absence T3, yet were impaired T3-driven gene activation and functioned as dominant-negative inhibitors wild-type activity. Intriguingly, TRalpha1 exerted interference at T3 concentrations tested, whereas TRbeta1 dominant-negatives only low intermediate concentrations, reverting transcriptional activators higher levels. The relative affinity SMRT versus N-CoR corepressors was detectably altered several TRs, suggesting changes corepressor preference recruitment compared wild type. Several TRalpha mutations also DNA recognition properties encoded receptors, indicating that may regulate distinct set from those regulated by TRs. Finally, TRs interfere with c-Jun/AP-1 function T3-dependent fashion suppress anchorage-independent growth when ectopically expressed HepG2 cells, least certain did not exert inhibitory These alterations regulation appear likely contribute oncogenesis reprogramming differentiation proliferative hepatocytes which expressed.