薯蓣皂苷元调控NF-κB信号网络逆转甲状腺未分化癌肿瘤干细胞紫杉醇耐药的作用机制研究

Anaplastic thyroid carcinoma is one of the most aggressive malignancies. At present, paclitaxel, a commonly used chemotherapy drug, is easily lead to the drug resistance, which seriously affects clinical efficacy. A large number of studies have shown that tumor resistance is rooted in the resistance of cancer stem cells. Activation of NF-κB signaling network is an important mechanism of tumor resistance, and inhibiting NF-κB signaling pathway can inhibit cancer stem cells of anaplastic thyroid carcinoma. On the basis of theory and practice in the Chinese medicine,we found that Dioscorea nipponica Makino containing (Diosgenin as the active ingredient) was a special drug to treat anaplastic thyroid carcinoma.At the same time,the clinical application showed that the paclitaxel combined wtih Dioscorea nipponica Makino had better clinical effect on anaplastic thyroid carcinoma patients. The preliminary cell experiments of the research group have shown that Diosgenin can reverse the resistance to paclitaxel by regulating the NF-κB. In order to verify the hypothesis in this study, we use flow cytometry to sort cancer stem cells of anaplastic thyroid carcinoma (SP cells), and quantify the effect of Diosgenin on the reversing the resistance to paclitaxel in cancer stem cells of anaplastic thyroid carcinoma in vitro and in vivo. Meanwhile,we explore the relevant molecular mechanisms through researching the regulation of NF-κB signaling networks. The research has a great significance on the development of new drugs for anaplastic thyroid carcinoma and the modernization of traditional Chinese medicine.

甲状腺未分化癌恶性程度高，目前常用化疗药物紫杉醇易耐药，严重影响疗效。研究表明：肿瘤耐药根源于肿瘤干细胞的耐药性；NF-κB信号网络激活是肿瘤耐药的重要机制，干预NF-κB信号通路可抑制肿瘤干细胞。穿山龙（薯蓣皂苷元为活性成分）是根据中医理论及实践发掘出的甲状腺未分化癌治疗专病专药，同时临床应用提示紫杉醇化疗联合穿山龙治疗甲状腺未分化癌具有更好的临床疗效。前期细胞实验表明，薯蓣皂苷元可调控NF-κB靶点改善甲状腺未分化癌紫杉醇耐药。在此基础上，提出科学假说：薯蓣皂苷元调控NF-κB信号网络逆转甲状腺未分化癌肿瘤干细胞紫杉醇耐药。为验证假说，本课题应用流式细胞仪分选甲状腺未分化癌肿瘤干细胞（SP细胞），拟在细胞和动物模型中，量化评估薯蓣皂苷元逆转肿瘤干细胞紫杉醇耐药的效应，从NF-κB靶点的信号网络调控角度来阐明相关分子机制。本研究对抗甲状腺未分化癌新药研发及中医药现代化研究具有重要的意义。

甲状腺未分化癌恶性程度高，目前常用化疗药物紫杉醇易耐药，严重影响疗效。本研究在细胞和动物模型实验中，评估薯蓣皂苷元逆转甲状腺未分化癌耐药，改善紫杉醇疗效的作用；通过RNA测序生信分析方法筛选薯蓣皂苷元干预后耐药相关差异化基因；根据生信分析结果，阐明薯蓣皂苷元调控活化的STAT3/NF-κB信号通路，干预增殖凋亡和逆转耐药的分子机制，阐明薯蓣皂苷元调控NOX5基因表达的作用机制；初步探索了薯蓣皂苷元调控肿瘤干细胞标志物CD133表达的作用。研究结果提示薯蓣皂苷元是一种可逆转甲状腺未分化癌紫杉醇耐药，对紫杉醇化疗具有增效作用的中药单体，具有一定的临床转化和应用价值。本研究对抗甲状腺未分化癌新药研发及中医药现代化研究具有重要的意义。