PPARgamma insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-kappaB signaling pathway.
The molecular genetic events underlying thyroid carcinogenesis are poorly understood. Mice harboring a knock-in dominantly negative mutant thyroid hormone receptor beta (TRbetaPV/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 (PPARgamma) could function as a tumor suppressor in thyroid cancer in vivo. Using the offspring from the cross of TRbetaPV/+ and PPARgamma+/- mice, we found that thyroid carcinogenesis progressed significantly faster in TRbetaPV/PV mice with PPARgamma insufficiency from increased cell proliferation and reduced apoptosis. Reduced PPARgamma protein abundance led to the activation of the nuclear factor-kappaB signaling pathway, resulting in the activation of cyclin D1 and repression of critical genes involved in apoptosis. Treatment of TRbetaPV/PV mice with a PPARgamma agonist, rosiglitazone, delayed the progression of thyroid carcinogenesis by decreasing cell proliferation and activation of apoptosis. These results suggest that PPARgamma is a critical modifier in thyroid carcinogenesis and could be tested as a therapeutic target in thyroid follicular carcinoma.
Kato
Y
Y
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
Ying
H
H
Zhao
L
L
Furuya
F
F
Araki
O
O
Willingham
M C
MC
Cheng
S-Y
SY
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000378:metabolism*
D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D037042:Thyroid Hormone Receptors beta; D000077154:Rosiglitazone; D019938:Cyclin D1