Involvement of glycogen synthase kinase-3beta signaling and aberrant nucleocytoplasmic localization of retinoblastoma protein in tumor promotion in a rat two-stage thyroid carcinogenesis model.
To investigate the cell cycle kinetics during the tumor promotion process induced by hypothyroidism in a rat model of thyroid follicular cell carcinogenesis, immunohistochemical analysis of cell cycle molecules and related signaling molecules was performed in conjunction with analysis of cell proliferation activity in an initiation-promotion model. Male F344 rats were injected with N-bis(2-hydroxypropyl)nitrosamine, and one week later treated with 6-propyl-2-thiouracil (PTU) at 12ppm in the drinking water for 4, 10 or 15 weeks. At each time point, proliferative lesions increased the expression of cyclin A, cyclin D, cyclin E and cyclin-dependent kinase (Cdk)-2, in association with the development of lesion stages from the early focal hyperplasia to the late carcinoma, while a subpopulation of proliferative lesions showed decreased numbers of both cell division cycle-2- and Ki-67-positive cells at week 15 compared with that at week 10, suggesting a reduced promoting effect of serum thyroid-stimulating hormone in the sensitive cellular population after long-term exposure to PTU. On the other hand, increased immunolocalization of phosphorylated and inactive glycogen synthase kinase (GSK)-3beta was observed in a subpopulation of proliferative lesions, in parallel with the cyclins and Cdk2. Nuclear immunoreactivity of phosphorylated and inactive retinoblastoma (Rb) protein was also increased in association with lesion development, with carcinomas showing increased cytoplasmic localization. The results suggest that proliferative lesions activate the cell cycle machinery following tumor promotion via a regulatory mechanism involving inactivation of GSK3beta and Rb protein, the latter signaling mechanism involving its aberrant nucleocytoplasmic transport for the acquisition of a malignant phenotype.
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Kyohei
K
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Saegusa
Yukie
Y
Nishimura
Jihei
J
Dewa
Yasuaki
Y
Kemmochi
Sayaka
S
Kawai
Masaomi
M
Harada
Tomoaki
T
Mitsumori
Kunitoshi
K
Shibutani
Makoto
M
D018263:Adenocarcinoma, Follicular / Q000139:chemically induced / Q000378:metabolism; D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D008297:Male; D009602:Nitrosamines / Q000633:toxicity; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013889:Thiouracil / Q000633:toxicity; D013964:Thyroid Neoplasms / Q000139:chemically induced / Q000378:metabolism*
D002273:Carcinogens; D018797:Cell Cycle Proteins; D009602:Nitrosamines; D016160:Retinoblastoma Protein; D013889:Thiouracil; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3