分化型甲状腺癌碘-131治疗抵抗发生机制及其逆转的研究

项目名称： 分化型甲状腺癌碘-131治疗抵抗发生机制及其逆转的研究

项目编号： No.81471692

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 匡安仁

作者单位： 四川大学

项目金额： 80万元

中文摘要： 探讨131I治疗和TSH抑制治疗、BRAF和RAS突变、碘代谢关键分子表达与DTC131I治疗抵抗之间的关系及其机制，试图证明反复131I治疗和长期TSH抑制是导致DTC131I治疗抵抗暨DTC失分化原因的假设，为临床合理制定131I和TSH抑制治疗提供实验和临床依据。TTF-1上调NIS表达，Pax-8上调Tg和TPO表达，以survivin启动子调控功能基因（ＮＩＳ）与调控基因（ＴＴＦ－１和Pax-8）联合转染，实现转染基因在DTC细胞的靶向性特异表达，提高摄取131I并延长有效T1/2；将抑制DNA甲基化的5－氮胞苷、抑制组蛋白脱乙酰化的TSA、上调RA核受体RARB和RXRG的蓓萨罗丁与RA，Dex进行多重组合优选，探讨联合诱导分化逆转DTC131I治疗抵抗；鉴于DTC131I抵抗的多种机制共存，所以联合基因转染和药物诱导多种手段，希在逆转DTC131I抵抗获突破进展

中文关键词： 分化型甲状腺癌；放射性碘治疗；碘-131；治疗抵抗；分子机制

英文摘要： The objectives of this project are to investigate the molecular mechanism of radioiodine therapy resistance and the reverse for differentiated thyroid carcinoma (DTC).It will be demonstrated that 131I therapy and TSH inhibition may be the causes to lead to radioiodine therapy resistance of DTC.The relationship between 131I treatment,TSH inhibition,BRAF or RAS mutation,and expression of the key moleculars of iodine metabolism with DTC radioiodine therapy resistance will be studied.The molecular mechanism of DTC radioiodine therapy resistance will be clarified to give the evidences for the treatment protocols optional of DTC. The TTF-1 gene is an upregulator of NIS and the Pax-8 gene is an upregulator of Tg and TPO.So,co- transfection of TTF-1, Pax-8 and NIS genes to radioiodine therapy resistance DTC can get synergistic effect.The DTC tumor-targeting adenovirus carriers will be developed which carry the NIS,TTF-1,and Pax-8 genes under control of the survivin promoter for reconstruction of iodine metabolism and the reverse of DTC radioiodine therapy resistance. The BRAF and RAS mutations, which mainly lead to DNA methylation and histone deacetylation, are main gene events to decrease expression of the key moleculars of iodine metabolism of DTC. Trichostatin A (TSA) is a demethylation agent , 5-azacytidine is a deacetylase inhibitor and bexarotene retorates RARB and RXRG receptors. The ability of DTC iodine uptake may be increased markedly because of the combination inducing of TSA, 5-azacytidine, bexarotene,and RA as well as Dex for redifferentiation of DTC.

英文关键词： differentiated thyroid cancer;radioiodine therapy;radioiodine-131 therapy resistance;molecular mechanism