Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma

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Abstract
Thyroid hormone (T 3 ) regulates proliferation and differentiation of cells, via its nuclear receptors (TRs). These processes have been shown to be abnormally regulated during carcinogenesis. We have previously found aberrant expression of TRα and TRβ mRNAs in renal clear cell carcinoma (RCCC), suggesting possible involvement of TRs in the carcinogenesis of RCCC. To understand the molecular actions of TRs in RCCC, cDNAs for TRβ1 and TRα1 were cloned from 22 RCCC tissues and 20 surrounding normal tissues. Mutations were found in seven TRβ1 and three TRα1 cDNAs. Two TRβ1 cDNAs had a single mutation, while five TRβ1 and three TRα1 had two or three mutations. Most of the mutations were localized in the hormone-binding domain. Using the TRs prepared by in vitro transcription/translation, we found that these mutations led to a loss of T 3 binding activity and/or impairment in binding to thyroid hormone response elements (TREs). Furthermore, nuclear extracts from RCCC tissues also exhibited impairment in binding to TREs. These results indicate that the normal functions of TRs in RCCC tissues were impaired. Together with the aberrant expression patterns, these mutated TRs could contribute to the carcinogenesis of RCCC.

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