Lan L, Deng W, Chen H L, Huo L L, Deng L L, Zhang G Y, Luo Y
Department of Endocrinology, Beijing Jishuitan Hospital, Beijing 100035, China.
Zhonghua Yi Xue Za Zhi. 2016 Feb 23;96(7):553-8. doi: 10.3760/cma.j.issn.0376-2491.2016.07.014.
To determine whether all-trans retinoic acid (ATRA) could improve iodine uptake via repressing transcriptional activity of β-catenin in thyroid cancer cells.
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, epithelial-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.
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).
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.
确定全反式维甲酸（ATRA）是否可通过抑制甲状腺癌细胞中β-连环蛋白的转录活性来提高碘摄取。
首先在未分化的人甲状腺癌细胞系SW1736中建立酒精、ATRA以及β-连环蛋白短发夹RNA转染三种处理模型。然后在上述三种细胞模型中进一步检测碘化钠转运体（NIS）、β-连环蛋白及其调节因子、上皮-间质转化（EMT）表型、侵袭和转移相关蛋白的表达。之后，在体外和体内试验中比较分析ATRA对NIS功能表达、碘摄取能力、肿瘤生长曲线以及放射性碘诱导的治疗效果的影响。
用ATRA处理后，β-连环蛋白的转录活性通过下调β-连环蛋白Ser45、Y654和糖原合成酶激酶-3β（GSK-3β）Ser9的磷酸化而降低。此外，ATRA有效上调了NIS的蛋白水平，并逆转了酒精处理细胞中的EMT表型，表现为E-钙黏蛋白和细胞角蛋白18上皮表达缺失，波形蛋白、尿纤溶酶原激活剂（uPA）、uPA受体和纤连蛋白表达异常。与酒精处理组相比，ATRA处理细胞的体外增殖和侵袭潜能均显著降低（均P<0.05），体外碘摄取增加约3.5倍（P=0.007）。在ATRA处理的动物模型中，放射性碘（131I）治疗显著抑制了肿瘤生长潜能和肿瘤质量（均P<0.05）。
ATRA可通过下调β-连环蛋白的转录活性增加NIS的功能表达，并提高人未分化甲状腺癌对放射性碘的同位素敏感性。
