In vivo model mouse study to examine the effect of alteration of endogenous endocrine status in thyroid tumorigenesis

本研究的目的是建立甲状腺癌转基因小鼠模型，并研究一种新型的选择性核因子κ B（NF-κB）抑制剂去羟甲基表氧喹诺霉素（DHMEQ）对甲状腺癌转基因小鼠模型的影响。一种是BRAF转基因小鼠，另一种是Ret/PTC转基因小鼠。这两种转基因小鼠在出生后4周内都会发生乳头状甲状腺癌。我们研究了新型NF-κB抑制剂DHMEQ对BRAF或RET转基因小鼠体内甲状腺癌的影响。结果：DHMEQ处理体外甲状腺癌细胞，可抑制NF-κB DNA结合活性，并以剂量和时间依赖性方式诱导细胞凋亡。然而，在体内研究中，DHMEQ不能抑制转基因小鼠甲状腺癌中NF-κB的活性。实验二：利用Cre-Lox-P系统建立新型甲状腺癌小鼠模型，该系统可以随时表达目的基因。建立了Cre基因和BRAF-Lox-P基因双转基因小鼠。然而，小鼠在诱导后不会发生甲状腺癌。

The aim of the study is to establish transgenic mice that develop thyroid cancer and then to examine the effects of a novel selective nuclear factor kappa B(NF-κB)inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), which change various cytokines status in vivo, in the mouse model.First Experiment : We prepared two types of transgenic mice. One is BRAF transgenic mice and another is Ret/PTC transgenic mice. Both transgenic mice develop papillary thyroid cancer within 4 weeks after birth. We examined the effect of DHMEQ, which is novel NF-κB inhibitor, to thyroid carcinomas developed in BRAF or RET-transgenic mice in vivo.Results : Treatment with DHMEQ inhibited NF-κB DNA binding activity and induced apoptosis in dose and time dependent manner in thyroid carcinoma cells in vitro. However, in the in vivo study, DHMEQ could not suppress the NF-κB activity in thyroid carcinomas in the transgenic mice. Through the animal experiments, DHMEQ did not show any side effects in treated mice.Second Experiment : We tried to establish novel thyroid carcinoma model mice using Cre-Lox-P system, which is allowed to express the interest gene at any time we want. We could establish the double transgenic mice that have Cre gene and BRAF-Lox-P gene. However, the mice could not develop thyroid carcinoma after induction.