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Published on: February 8, 2020
Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma
Yuji Kamiya1, Monika Puzianowska-Kuznicka, Peter McPhie
1Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255, USA.
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 TRalpha and TRbeta 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 TRbeta1 and TRalpha1 were cloned from 22 RCCC tissues and 20 surrounding normal tissues. Mutations were found in seven TRbeta1 and three TRalpha1 cDNAs. Two TRbeta1 cDNAs had a single mutation, while five TRbeta1 and three TRalpha1 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.
Insights
Mutations in thyroid hormone receptors (TRs) are found in renal clear cell carcinoma (RCCC), impairing their function. These TR mutations may contribute to RCCC development.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Thyroid hormone (T3) regulates cell proliferation and differentiation through nuclear receptors (TRs).
- Aberrant regulation of these processes is implicated in carcinogenesis.
- Previous studies noted altered TRalpha and TRbeta mRNA expression in renal clear cell carcinoma (RCCC).
Purpose of the Study:
- To investigate the molecular mechanisms of TRs in RCCC development.
- To identify mutations in TRbeta1 and TRalpha1 within RCCC tissues.
Main Methods:
- Cloning of TRbeta1 and TRalpha1 cDNAs from RCCC and normal kidney tissues.
- Mutation analysis of cloned cDNAs.
- In vitro transcription/translation to assess TR protein function (T3 binding, TRE binding).
- Analysis of TRE binding in nuclear extracts from RCCC tissues.
Main Results:
- Mutations were identified in 7 TRbeta1 and 3 TRalpha1 cDNAs from RCCC.
- Most mutations were located in the hormone-binding domain.
- Mutated TRs exhibited reduced T3 binding and/or impaired binding to thyroid hormone response elements (TREs).
- Nuclear extracts from RCCC tissues showed impaired TRE binding.
Conclusions:
- Normal TR function is compromised in RCCC tissues.
- Mutated TRs, alongside aberrant expression, likely contribute to RCCC carcinogenesis.
- TRs represent a potential target for RCCC research and therapy.
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