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Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire

Oncogene volume 28, pages 4162–4174 (2009)Cite this article

Abstract

Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that control multiple aspects of normal physiology and development. Mutations in TRs have been identified at high frequency in certain cancers, including human hepatocellular carcinomas (HCCs). The majority of HCC–TR mutants bear lesions within their DNA recognition domains, and we have hypothesized that these lesions change the mutant receptors’ target gene repertoire in a way crucial to their function as oncoproteins. Using stable cell transformants and expression array analysis, we determined that mutant TRs isolated from two different HCCs do, as hypothesized, display a target gene repertoire distinct from that of their normal TR progenitors. Only a subset of genes regulated by wild-type TRs was regulated by the corresponding HCC–TR mutants. More surprisingly, the HCC–TR mutants also gained the ability to regulate additional target genes not recognized by the wild-type receptors, and were not simply restricted to repression, but could also activate a subset of their target genes. We conclude that the TR mutants isolated from HCC have sustained multiple alterations from their normal progenitors that include not only changes in their transcriptional outputs, but also changes in the genes they target; both are likely to contribute to neoplasia.

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Acknowledgements

We are extremely grateful to Liming Liu for excellent technical assistance, Michael L Goodson for expert assistance in analysis of the array data, and Elsie L Campbell for helpful discussions. This work was supported by the Public Health Service/National Cancer Institute award R37-CA53394 and by the UC Davis Cancer Center Gene Expression Resource (NCI P30-CA93373). IHC was supported in part by a PHS pre-doctoral training award, T32-GM007377, from the National Institute of General Medical Sciences.

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  1. Department of Microbiology, College of Biological Sciences, University of California at Davis, Davis, CA, USA

    I H Chan & M L Privalsky

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Correspondence to M L Privalsky.

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Chan, I., Privalsky, M. Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire. Oncogene 28, 4162–4174 (2009). https://doi.org/10.1038/onc.2009.265

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