细胞凋亡基因GRIM-19对甲状腺癌细胞碘代谢机制的研究

Treating dedifferentiated thyroid cancer (dDTC),alone or in combination with retinoic acid, trichostatin endostatin A and dexamethasone, was cultured in vitro on cells inducing to differentiate effects, but limited role was in vivo with the efficiency of 20-40%. Signal transducers and activators of transcription 3(STAT3) mediated JAK-STAT signaling pathway, the sustained activation of which induced the lack of apoptosis relating closely to tumor. The apoptosis gene of GRIM-19 can specifically combine with STAT3,which lowered inhibitor of apoptosis genes and cell cycle to regulate gene expression and relieve the suppression of apoptosis in STAT3. Retinoic acid/interferon (RA/IFN) combined induction of apoptosis,its mechanism may increase the expression of GRIM-19, RA can also be induced to differentiate to make dDTC iodine uptake capacity increase.RA/IFN jointed dual role of pro-apoptotic and differentiation induction in human thyroid cancer cell lines, The key molecule mRNA and protein expression,associated with apoptosis and iodine metabolism,were determined in vivo and in vitro experiments from the gene and protein levels. .In conclution, to investigate the influence of GRIM-19 to iodine metabolism in thyroid cancer, a new model of pro-apoptotic therapy combined with internal radiation therapy will be established to provide novel ideas for the treatment of thyroid cancer.

单独或联合应用维甲酸、曲古抑素A、地塞米松等诱导剂，治疗失分化甲状腺癌（dDTC），体外培养对细胞有诱导分化效果，但体内作用有限，有效率20-40%。转录信号转导子与激活子3（STAT3）及其介导的JAK-STAT信号通路，其持续激活引起的凋亡不足与肿瘤发生密切相关。细胞凋亡基因GRIM-19，与STAT3特异性结合，下调凋亡抑制基因和细胞周期调节基因的表达，解除STAT3的抑凋亡作用。维甲酸/干扰素(RA/IFN)合并诱导细胞凋亡，其机制可能与上调GRIM-19表达有关，RA还可诱导分化使dDTC摄碘能力增加。RA/IFN联合有促凋亡和诱导分化的双重作用，在人甲状腺癌细胞株中，通过体内和体外实验分别测定与凋亡和碘代谢相关的关键分子mRNA和蛋白表达，从基因和蛋白水平比对，探讨GRIM-19对甲状腺癌细胞碘代谢机制的影响，建立促凋亡治疗与内照射治疗联合应用新模式，为甲状腺癌治疗提供新思路。

在体外细胞模型上筛选出维甲酸（ATRA）与干扰素（IFN）联合用药的最佳药物浓度为ATRA 2µM，IFN-α2a 1500IU/mL。生长抑制实验显示，联合用药72h对甲癌细胞FTC-133的生长抑制率可达30.1±12.17%，对ARO的生长抑制率达46.6±9.87%。125I摄取实验证实联合用药组与单药组比较，甲状腺癌细胞摄碘能力明显提高。125I流出实验显示联合用药组与单药组比较，各组间细胞内药物半衰期无统计学差异。联合用药后仅能提高细胞摄碘能力，不能延长碘在细胞内的停留过程。裸鼠体内实验证实，不同用药方案对裸鼠皮下甲状腺肿瘤的生长产生不同影响，联合用药组的肿瘤体积小于单药组。肿瘤组织的免疫组化结果显示，肿瘤组织中均可检测到GRIM-19表达，且联合用药组GRIM-19表达高于单药组，但STAT3的表达无明显差异。 本研究运用体外和体内实验证实GRIM-19促凋亡治疗与甲状腺癌131I治疗进行联合的协同作用，为甲状腺癌治疗提供新思路。