Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

Area of Science:

• Endocrinology
• Molecular Biology
• Oncology

Background:

• Aberrant thyroid hormone receptors (TRs) are implicated in over 70% of human hepatocellular carcinomas (HCCs).
• Understanding the molecular mechanisms of these TR mutants is crucial for comprehending their role in liver cancer development.

Purpose of the Study:

• To investigate the molecular properties of TR mutants found in HCC.
• To elucidate how these mutants affect target gene regulation and cellular functions.

Main Methods:

• Analysis of a panel of HCC-associated TR mutants.
• Assessment of TRs' ability to repress/activate target genes in the presence and absence of thyroid hormone (T3).
• Evaluation of dominant-negative interference with wild-type TR activity and corepressor binding affinities.

Main Results:

• HCC TR mutants retained repression but showed impaired T3-driven activation, acting as dominant-negative inhibitors.
• TRalpha1 mutants were consistently dominant-negative, while TRbeta1 mutants' activity varied with T3 concentration.
• Mutations altered corepressor binding and DNA recognition, suggesting regulation of distinct gene sets.
• Certain HCC TR mutants failed to suppress anchorage-independent growth, unlike wild-type TRs.

Conclusions:

• HCC-associated TR mutations alter transcriptional regulation and DNA binding properties.
• These alterations likely contribute to hepatocarcinogenesis by reprogramming hepatocyte differentiation and proliferation.
• Mutant TRs represent potential therapeutic targets in liver cancer.