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

Thyroid hormone receptor beta 1 (TF beta 1) is a hormone-dependent transcription factor activated by 3.5,3'-1-truodothyronine (T3) TR beta 1 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 TR beta 1 expression in clear cell renal cell cancer (ccRCC) results from regulatory effects of TR beta 1 5' and 3'UTRs on protein translation. We determined TR beta 1 expression and alternative splicing of TR beta 1 5' and 3' UTRs in ccRCC and control tissue together with expression of the type 1 deiodinase enzyme (coded by DIO1, a TR beta 1 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 TR beta 1 3'UTR) were also determined TR beta 1 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 TR beta 1 UTR variants indicated that reduced TR beta 1 expression may be maintained in ccRCC by posttranscriptional mechanisms involving 5'UTRs and miRNA-204 The tumor suppressor activity of TR beta 1 indicates that reduced TR beta 1 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. (C) 2010 Elsevier B.V. All rights reserved.