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PPARgamma insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-kappaB signaling pathway.

Abstract
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.
AuthorsY Kato, H Ying, L Zhao, F Furuya, O Araki, M C Willingham, S-Y Cheng
JournalOncogene (Oncogene) Vol. 25 Issue 19 Pg. 2736-47 (May 04 2006) ISSN: 0950-9232 [Print] England
PMID16314832 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Chemical References
  • NF-kappa B
  • PPAR gamma
  • Thiazolidinediones
  • Thyroid Hormone Receptors beta
  • Rosiglitazone
  • Cyclin D1
Topics
  • Animals
  • Apoptosis
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cyclin D1 (metabolism)
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Mutant Strains
  • NF-kappa B (genetics, metabolism)
  • PPAR gamma (genetics, physiology)
  • Rosiglitazone
  • Signal Transduction
  • Thiazolidinediones (pharmacology)
  • Thyroid Hormone Receptors beta (genetics, physiology)
  • Thyroid Neoplasms (metabolism)

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