Journal Article

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

Yuji Kamiya, Monika Puzianowska-Kuznicka, Peter McPhie, Janusz Nauman, Sheue-yann Cheng and Alicja Nauman

in Carcinogenesis

Volume 23, issue 1, pages 25-33
Published in print January 2002 | ISSN: 0143-3334
Published online January 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.1.25
Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma

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Thyroid hormone (T3) 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 T3 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.

Keywords: EMSA, electrophoresis mobility shift assay; HCC, hepatocellular carcinoma; LOH, loss of heterozygosity; NFTs, non-functioning tumors; RCCC, renal clear cell carcinoma; RTH, thyroid hormone resistance syndrome; RXRs, retinoic X receptors; T3, thyroid hormone; TRs, thyroid hormone nuclear receptors; TRE, thyroid hormone response element; VHL, von Hippel–Lindau tumor suppressor gene; w-TR, wild-type TR.

Journal Article.  8479 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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