Related Experiment Videos
Functionally impaired TR mutants are present in thyroid papillary cancer
Monika Puzianowska-Kuznicka1, Agnieszka Krystyniak, Agnieszka Madej
1Department of Endocrinology, Medical Research Center, Polish Academy of Sciences, 02-097 Warsaw, Poland. monika@amwaw.edu.pl
Abstract:
TRs are transcription factors that regulate cell proliferation, differentiation, and apoptosis. They are cellular homologs of the transcriptionally inactive viral oncogene v-erbA. We tested the hypothesis that the functions of TRs could be impaired in cancer tissues as a result of aberrant expression and/or somatic mutations. As a model system, we selected human thyroid papillary cancer, in which the most common abnormalities, RET/papillary thyroid cancer rearrangements (fusion of RET kinase domain to the activating domains of other genes), were found in 40--45% of cases. We found that the mean expression levels of TR beta mRNA and TR alpha mRNA were significantly lower, whereas the protein levels of TR beta 1 and TR alpha 1 were higher in cancer tissues than in healthy thyroid. Sequencing of TR beta 1 and TR alpha 1 cDNAs, cloned from 16 papillary cancers, revealed that mutations affected receptor amino acid sequences in 93.75% and 62.5% of cases, respectively. In contrast, no mutations were found in healthy thyroid controls, and only 11.11% and 22.22% of thyroid adenomas had such TR beta 1 or TR alpha 1 mutations, respectively. The majority of the mutated TRs lost their trans-activation function and exhibited dominant negative activity. These findings suggest a possible role for mutated thyroid hormone receptors in the tumorigenesis of human papillary thyroid carcinoma.
Insights
Mutated thyroid hormone receptors (TRs) show impaired function in thyroid cancer. These TRs may play a role in papillary thyroid carcinoma development, impacting cell processes.
Area of Science:
- Molecular Biology
- Oncology
- Endocrinology
Background:
- Thyroid hormone receptors (TRs) are crucial transcription factors regulating cell proliferation, differentiation, and apoptosis.
- TRs are cellular homologs of the viral oncogene v-erbA.
- Cancer may involve impaired TR function due to aberrant expression or mutations.
Purpose of the Study:
- To investigate the hypothesis that TR functions are impaired in thyroid cancer tissues.
- To analyze TR expression and mutation status in human papillary thyroid carcinoma.
- To determine the functional consequences of TR mutations in tumorigenesis.
Main Methods:
- Analysis of TR beta and TR alpha mRNA and protein levels in cancerous versus healthy thyroid tissues.
- Sequencing of TR beta 1 and TR alpha 1 cDNAs from papillary thyroid cancer and control tissues.
- Assessment of trans-activation function and dominant-negative activity of mutated TRs.
Main Results:
- Significantly lower TR beta and TR alpha mRNA levels, but higher TR beta 1 and TR alpha 1 protein levels in cancer tissues.
- High prevalence of TR beta 1 (93.75%) and TR alpha 1 (62.5%) mutations in papillary thyroid cancers.
- Mutated TRs frequently lost trans-activation function and exhibited dominant-negative activity, unlike in healthy thyroids or adenomas.
Conclusions:
- Mutations in thyroid hormone receptors are common in papillary thyroid carcinoma.
- Altered TR expression and function may contribute to papillary thyroid carcinoma development.
- Mutated TRs possess impaired trans-activation and dominant-negative properties, suggesting a role in tumorigenesis.