中文摘要：

目的观察全反式维甲酸（ATRA）能否通过遏制β-catenin转录活性影响甲状腺癌的同位素敏感性。方法分别建立3组细胞模型：以1％的无水乙醇处理未分化甲状腺癌细胞株SW1736（阴性对照组），以1μmol／L ATRA处理SW1736（ATRA组），pSUPER／β-catenin封闭质粒转染SW1736（阳性对照组）。Western印迹法检测钠碘转运体（NIS）、β-catenin信号通路关键调节蛋白的表达变化、上皮细胞间质转化（EMT）属性蛋白和转移侵袭相关功能蛋白的表达变化。Transwell和MTT法对比各组细胞的体外侵袭和增殖能力的差异。摄碘试验进一步评价各组细胞体外摄碘能力的变化。制作重症联合免疫缺陷（SCID）小鼠皮下瘤模型，观察肿瘤生长曲线、肿瘤质量以及对放射碘剂的治疗反应等方面的差异。结果与阴性对照组细胞模型相比，经ATRA处理后，β—catenin Ser45、Y654以及GSK-38Ser9位点磷酸化水平均显著下降，遏制了β-catenin由胞质“入核”的效率，且上皮表型蛋白[包括E-钙黏素（E-cadherin）和细胞角蛋白（CK）18]表达转阳，而间质属性蛋白[包括波形蛋白（Vimentin）、尿激酶型纤溶酶原激活因子（uPA）及其受体uPAR、纤维连接蛋白（Fibronectin）]则表达转阴，钠碘转运体（NIS）表达水平显著上升，ATRA处理后72h，体外增殖和侵袭能力分别下降39％和37％（均P〈0．05），细胞摄碘能力增强3．5倍（P=0．007），这些变化趋势与阳性对照组细胞模型一致。ATRA组小鼠较阴性对照组小鼠对^131I治疗更加敏感，肿瘤体积增长趋势被显著抑制（P=0．004），并显示与阳性对照组小鼠相似的^131I治疗趋势，ATRA组小鼠的平均瘤体质量也比阴性对照组减少47．8％（P=0．035），并与阳性对照组接近（P=0．091）。结论ATRA能够通过遏制β—catenin核易位效率并降低其转录活性，增高NIS表达水平，改善未分化甲状腺癌同位

英文摘要：

Objective To determine whether all-trans retinoic acid （ATRA） could improve iodine uptake via repressing transcriptional activity of β-catenin in thyroid cancer cells. Methods Three kinds of treatment models were firstly established with alcohol, ATRA, and transfection of β-catenin shRNA in undifferentiated human thyroid cancer cell line-SW1736. Then the expressions of sodium iodide symporter （NIS）, β-catenin and its regulating factors, epithehal-mensechymal transition （EMT） -phenotype, invasion and metastasis associated proteins were further measured in above three cell models. After that, the influence of ATRA on the functional expression of NIS, iodine uptake potency, tumor growth curve and treatment effect inducing by radioactive iodine was comparatively analyzed in vitro and in vivo trials. Results After treated with ATRA, transcriptional activity of β-catenin decreased by downregulating phosphorylation of β-catenin Ser45,Y654 and GSK-3β Ser9. Additionally, ATRA effectively upregulated the protein level of NIS, and reversed EMT phenotype in alcohol treated cells, with absence in epithelial expression of E-cadherin and cytokeratin 18, as well as abnormal expression of Vimentin, urinary plasminogen activator （uPA）, uPAR and Fibronectin. Compared with alcohol-treated group, both in vitro proliferation and invasion potential of ATRA treated cells markedly decreased （ all P 〈 0. 05 ）, and iodine uptake in vitro increased about 3.5-folds （P = 0. 007 ）. In ATRA-treated animal model, tumor growth potential and tumor mass were significantly inhibited by radio-iodine （ ^131 I） treatment （ all P 〈 0. 05 ）. Conclusions ATRA can increase functional expression of NIS via downregulating transcriptional activity of β-catenin and promote isotope sensitivity to radio-iodine in human undifferentiated thyroid cancer.