期刊
ONCOGENE
卷 25, 期 19, 页码 2736-2747出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209299
关键词
thyroid cancer; mutant thyroid hormone receptor; PPAR gamma; NF-kappa B; mouse model; apoptosis
资金
- Intramural NIH HHS Funding Source: Medline
The molecular genetic events underlying thyroid carcinogenesis are poorly understood. Mice harboring a knock-in dominantly negative mutant thyroid hormone receptor beta (TR beta(PV/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 gamma (PPAR gamma) could function as a tumor suppressor in thyroid cancer in vivo. Using the offspring from the cross of TR beta(PV/+) and PPAR gamma(+/-) mice, we found that thyroid carcinogenesis progressed significantly faster in TRbPV/PV mice with PPAR gamma insufficiency from increased cell proliferation and reduced apoptosis. Reduced PPAR gamma protein abundance led to the activation of the nuclear factor-kappa B signaling pathway, resulting in the activation of cyclin D1 and repression of critical genes involved in apoptosis. Treatment of TR beta PV/PV mice with a PPAR gamma agonist, rosiglitazone, delayed the progression of thyroid carcinogenesis by decreasing cell proliferation and activation of apoptosis. These results suggest that PPAR gamma is a critical modi. er in thyroid carcinogenesis and could be tested as a therapeutic target in thyroid follicular carcinoma.
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