Untranslated regions of thyroid hormone receptor beta 1 mRNA are impaired in human clear cell renal cell carcinoma

Thyroid hormone receptor β1 (TRβ1) is a hormone-dependent transcription factor activated by 3,5,3'-l-triiodothyronine (T3). TRβ1 functions as a tumor suppressor and disturbances of the THRB gene are frequent findings in cancer. Translational control mediated by untranslated regions (UTRs) regulates cell proliferation, metabolism and responses to cellular stress, processes that are involved in carcinogenesis. We hypothesized that reduced TRβ1 expression in clear cell renal cell cancer (ccRCC) results from regulatory effects of TRβ1 5′ and 3′UTRs on protein translation. We determined TRβ1 expression and alternative splicing of TRβ1 5′ and 3′UTRs in ccRCC and control tissue together with expression of the type 1 deiodinase enzyme (coded by DIO1, a TRβ1 target gene). Tissue concentrations of T3 (which are generated in part by D1) and expression of miRNA-204 (an mRNA inhibitor for which a putative interaction site was identified in the TRβ1 3′UTR) were also determined. TRβ1 mRNA and protein levels were reduced by 70% and 91% in ccRCC and accompanied by absent D1 protein, a 58% reduction in tissue T3 concentration and 2-fold increase in miRNA-204. Structural analysis of TRβ1 UTR variants indicated that reduced TRβ1 expression may be maintained in ccRCC by posttranscriptional mechanisms involving 5′UTRs and miRNA-204. The tumor suppressor activity of TRβ1 indicates that reduced TRβ1 expression and tissue hypothyroidism in ccRCC tumors is likely to be involved in the process of carcinogenesis or in maintaining a proliferative advantage to malignant cells.

Research Highlights
► TRβ1 mRNA and protein levels are significantly reduced in renal cancer.
► Loss of D1 and reduced level of intracellular T3 are found in kidney tumors.
► TRβ1 decrease in renal cancer is caused by miRNA-204 upregulation.
► 5′UTR and 3′UTR are involved in posttranscriptional TRβ1 regulation in renal cancer.
► Renal cancer is characterized by tissue hypothyroidism.