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Published on: August 23, 2019
Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene
1Department of Microbiology, College of Biological Sciences, University of California at Davis, Davis, CA 95616, USA.
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.
Insights
Mutated thyroid hormone receptors (TRs) in liver cancer (HCC) alter their gene targets, acting as oncoproteins. These cancer-associated TR mutants gain new functions, driving tumor development.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Thyroid hormone receptors (TRs) are crucial transcription factors regulating physiology and development.
- TR mutations are frequently found in cancers, particularly hepatocellular carcinoma (HCC).
Purpose of the Study:
- To investigate how mutations in TRs from HCC alter their target gene repertoire.
- To understand the role of altered TR function in hepatocellular carcinoma pathogenesis.
Main Methods:
- Stable cell transformants were created using HCC-derived TR mutants.
- Expression array analysis was employed to compare gene expression profiles.
Main Results:
- HCC-TR mutants exhibited a distinct target gene repertoire compared to wild-type TRs.
- Mutant TRs regulated a subset of wild-type TR targets and gained the ability to regulate novel genes.
- HCC-TR mutants could both activate and repress gene expression, not just repress.
Conclusions:
- TR mutants in HCC possess altered transcriptional outputs and target gene profiles.
- These alterations in TR function likely contribute to cancer development (neoplasia).
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