PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

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.