Regulation of AKR1B1 by thyroid hormone and its receptors

The objective of this study was to identify genes regulated by thyroid hormone (T₃) mediated by its receptor (TR) and associated with tumorigenesis. The gene encoding aldo-keto reductase family 1, member B1 (AKR1B1), as previously identified by c-DNA microarray, is known to be up-regulated by T₃ treatment. Enzyme AKR1B1 was elevated roughly 3-fold in HepG2-TRα1 cells at the protein level and 4.6-fold increase at the mRNA level after 48 h T₃ treatment. Similar findings were obtained from thyroidectomized rats after T₃ application. To identify and localize the critical TR element (TRE), series deletion of the promoter mutant were constructed and electrophoretic mobility shift assays were carried out. The TRE on the AKR1B1 promoter was localized to the -1099/-1028 region. Further, this study demonstrated that AKR1B1 over-expression in some types of hepatocellular carcinomas (HCCs) is TR-dependent and might play a crucial role in the development of HCC. Thus, T₃ regulates AKR1B1 gene expression via a TRE-dependant mechanism and associates liver cancer.