Abstract
The molecular genetic events underlying thyroid carcinogenesis are poorly understood. Mice harboring a knock-in dominantly negative mutant thyroid hormone receptor β (TRβPV/PV mouse) spontaneously develop follicular thyroid carcinoma similar to human thyroid cancer. Using this mutant mouse, we tested the hypothesis that the peroxisome proliferator-activated receptor γ (PPARγ) could function as a tumor suppressor in thyroid cancer in vivo. Using the offspring from the cross of TRβPV/+ and PPARγ+/− mice, we found that thyroid carcinogenesis progressed significantly faster in TRβPV/PV mice with PPARγ insufficiency from increased cell proliferation and reduced apoptosis. Reduced PPARγ protein abundance led to the activation of the nuclear factor-κB signaling pathway, resulting in the activation of cyclin D1 and repression of critical genes involved in apoptosis. Treatment of TRβPV/PV mice with a PPARγ agonist, rosiglitazone, delayed the progression of thyroid carcinogenesis by decreasing cell proliferation and activation of apoptosis. These results suggest that PPARγ is a critical modifier in thyroid carcinogenesis and could be tested as a therapeutic target in thyroid follicular carcinoma.
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Acknowledgements
We thank Dr Peter McPhie for the statistical analysis of the effect of rosiglitazone treatment on the pathological progression of TRβPV/PV mice. This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.
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Kato, Y., Ying, H., Zhao, L. et al. PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway. Oncogene 25, 2736–2747 (2006). https://doi.org/10.1038/sj.onc.1209299
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DOI: https://doi.org/10.1038/sj.onc.1209299
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