Overexpression of E2F1 in clear cell renal cell carcinoma: a potential impact of erroneous regulation by thyroid hormone nuclear receptors.

We show here that the promoter of E2F1 gene, encoding one of the key regulators of cell proliferation, is overly active in the presence of low amounts of triiodothyronine (T3) and in the presence of mutant thyroid hormone receptor. We also show that T3-thyroid hormone receptor pathway of regulation of molecular processes is disturbed in clear cell renal cell carcinoma (ccRCC) on several levels, including overexpression of thyroid hormone receptors and the disturbance of their binding to DNA and to the hormone. In comparison to the cancer-free kidneys and peritumoral respective control tissues, E2F1 mRNA and protein levels are significantly increased in cancer tissues. A significant correlation between E2F1 mRNA and protein levels has been found in both control types and ccRCCs. No correlation was observed between the amount of E2F1 mRNA and the amount of thyroid hormone receptors or their DNA or T3 binding activity, suggesting that the function of thyroid hormone receptors could be markedly disturbed in both tumor and peritumoral cells. In summary, we show that ccRCC is characterized by the overexpression of E2F1, which is likely a result of a deregulated control of T3-dependent molecular processes.