诺帝对大鼠C6脑胶质瘤的诱导分化治疗作用及对信号转导分子STAT3和p-STAT3蛋白表达的影响

Treatment of C6 orthotopic implantation in rat brains with Nordy and its effects on the expression of STAT3 and p-STAT3

目的研究诺帝对大鼠C6脑胶质瘤GFAP、Vimentin及信号传导和转录激活因子3(STAT3)和酪氨酸磷酸化STAT3(pSTAT3)表达水平影响,探讨恶性胶质瘤发生机制及诺帝诱导分化作用的分子机制。方法立体定向接种法将C6胶质瘤细胞悬液接种于雄性Wistar大鼠右脑尾状核,采用本室专利方法合成的抗胶质瘤新药诺帝(27和54mg/kg体重腹腔注射)作为治疗方法,观察移植瘤病理组织学和超微结构变化,检测胶质纤维酸性蛋白(GFAP)和vimentin两种分化标志物的表达,并观测细胞信号转导分子STAT3及其磷酸化状态pSTAT3蛋白表达水平。结果诺帝治疗组的抑瘤率分别为79.83%～97.74%,移植瘤体积明显减小,肿瘤无论在形态上还是免疫表型上均呈现诱导分化现象,GFAP表达增强,而vimentin表达降低,STAT3和pSTAT3平均光密度值也减低。结论诺帝对C6细胞的原位移植瘤具有诱导分化治疗作用,抑制STAT3表达及其酪氨酸磷酸化活性从而上调GFAP表达可能是其诱导分化治疗作用的机制之一。

Objective To test the effects of a synthetic compound Nordy on the expression of glial fibrillary acidic protein (GFAP), vimentin, signal transducer and activator of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) and to explore the mechanism of Nordy-induced differentiation. Methods 1×10 6 cells (10μl) of C6 glioma cell line for each rat were stereotactically implanted into the right caudate nuclei of male Wistar rats. A synthetic compound Nordy (27 and 54 mg/kg body weight) was used in the treatment of the implanted tumors formed by C6 cells. For evaluation of the effects of Nordy on the tumors, histopathology and ultrastructure were observed and immunocytochemical staining for GFAP, vimentin, STST3 and p-STAT3 were performed on the tumor tissues.Results The inhibition rates of Nordy-treated rats were 79.83% and 97.74% respectively. The implanted tumors were smaller in sizes, with appearance of morphology and immunostaining phonotypes, i.e., increased GFAP and decreased vimentin expression. Meanwhile, the expression levels of both STAT3 and p-STAT3 were also reduced. Conclusions Nordy had potential therapeutic effects on the malignant orthotopic C6 glioma in rat brains. Upregulation of GFAP through inhibition of STAT3 signaling might be one of its mechanism of the differentiation therapy.