Preventive Effects of Calcitriol on the Development of Capsular Invasive Carcinomas in a Rat Two-Stage Thyroid Carcinogenesis Model
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概要
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We have shown phosphoinositide 3-kinase (PI3K)/Akt signaling activation in thyroid capsular invasive carcinomas (CICs), which are highly induced by promotion with sulfadimethoxine (SDM) in a rat two-stage thyroid carcinogenesis model. To examine the potency of calcitriol, a synthetic vitamin D3 analog, on the development or progression of CICs, male F344 rats were injected with calcitriol (0.1 μg/kg body weight) three times a week intraperitoneally, during an entire period of SDM-promotion for 13 weeks (Experiment 1) or during the last 2 weeks of a 15-week SDM-promotion (Experiment 2). Initiation with N-bis(2-hydroxypropyl)nitrosamine preceded all treatments. In Experiment 1, long-term calcitriol treatment reduced the multiplicity of CICs, while cell proliferation activity, estimated by Ki-67 cell index in the induced CICs, was unchanged with SDM-promotion alone. Considering the strong dependency of promotion with SDM during the early stages on thyroid-stimulating hormone, the reduced multiplicity in Experiment 1 may be due to the effect on an early stage of neoplastic proliferation. Although the magnitude was mild, cell proliferation activity was decreased in existing CICs after short-term calcitriol treatment in Experiment 2, which was associated with a mild decrease in cyclin-dependent kinase-2-positive cells, cytoplasmic immunolocalization of phosphorylated, inactive, Rb protein and a mild increase in nucleocytoplasmic expression of p27kip1. Although the effect was mild at the late stage of SDM-promotion in this hypothyroidism-related thyroid carcinogenesis model, our results suggest that calcitriol targets cell proliferation via inhibition of a molecular cascade downstream of PI3K/Akt signaling, controlling G1/S transition.
著者
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KEMMOCHI Sayaka
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
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Mitsumori Kunitoshi
Laboratory Of Veterinary Pathology Division Of Animal Science Institute Of Symbiotic Science And Tec
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Nishikawa Akiyoshi
Division Of Pathology Biology Safety Research Center National Institute Of Health Sciences
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WOO Gye-Hyeong
Division of Pathology, National Institute of Health Sciences
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FUJIMOTO Hitoshi
Division of Pathology, National Institute of Health Sciences
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Shibutani Makoto
Laboratory Of Veterinary Pathology Tokyo University Of Agriculture And Technology
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Kemmochi Sayaka
Laboratory Of Veterinary Pathology Tokyo University Of Agriculture And Technology
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Hirose Masao
Food Safety Commission
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