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的转基因小鼠模型，并观察一种新型的选择性核因子kappaB(NF-κB)抑制剂脱羟甲基氧奎诺米星(DHMEQ)对小鼠体内多种细胞因子状态的影响。一组为BRAF转基因小鼠，另一组为Ret/PTC转基因小鼠。这两只转基因小鼠在出生后4周内都会患上乳头状甲状腺癌。结果：DHMEQ可抑制体外培养的甲状腺癌细胞的NF-κB结合活性，并以剂量和时间依赖的方式诱导甲状腺癌细胞的凋亡。但在体内实验中，二氢美其清不能抑制转基因小鼠甲状腺癌组织中核因子-κB的活性。通过动物实验，DHMEQ在治疗的小鼠身上没有表现出任何副作用。第二个实验：我们试图利用Cre-Lox-P系统建立新的甲状腺癌模型，该系统允许在我们想要的任何时间表达目的基因。我们可以建立Cre基因和BRAF-Lox-P基因的双转基因小鼠。然而，诱导后的小鼠不能形成甲状腺癌。

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.