紫草素对甲状腺肿瘤恶性行为的影响及其分子机制研究

发布时间：2017-12-28 11:11

本文关键词：紫草素对甲状腺肿瘤恶性行为的影响及其分子机制研究　出处：《西安交通大学》2017年博士论文　论文类型：学位论文

【摘要】：研究背景:甲状腺癌是内分泌系统最常见的恶性肿瘤,虽然80%以上的甲状腺肿瘤属高分化癌,通过手术及放射碘治疗,预后较好。但甲状腺肿瘤存在容易复发的特点,并存在病情进展为低分化或未分化癌的风险,分化差的甲状腺肿瘤手术及放化疗效果均不佳,生存率极低。因此,临床仍需寻找安全有效的内科治疗药物,以弥补现有治疗方案的缺陷。紫草素提取自中药紫草根,是一种萘醌类活性成分。紫草在传统中医应用于活血凉血、利大小肠、治疗斑疹不透、水火烫伤等。现代医学发现紫草素具有抗炎、灭病原微生物、抗血小板、抗癌等多种功效。其中抗癌功效已分别在直肠癌、黑色素瘤、白血病、乳腺癌以及肝癌等多种肿瘤中得以证实。但是,仍缺乏紫草素在甲状腺肿瘤治疗中的应用及研究报道。研究目的:本研究旨在揭示紫草素对甲状腺肿瘤生物学行为的影响,并揭示紫草素的抗癌机制。实验设计:本研究分别设计相应实验,检测紫草素对甲状腺肿瘤细胞的增殖、周期、凋亡、迁移及侵袭的影响,并构建裸鼠皮下移植瘤模型,检测紫草素在体内对甲状腺肿瘤细胞的作用,并通过检测细胞内各信号分子的含量及活性研究紫草素对肿瘤信号分子的调节作用。实验结果:本研究实验发现紫草素能够有效抑制甲状腺肿瘤细胞增殖,并呈良好的时间及剂量依赖关系。紫草素能够诱导甲状腺肿瘤细胞周期抑制及细胞凋亡,其中凋亡的诱导是通过活性氧产物(ROS)介导的DNA损伤及p53信号通路的激活而实现。同时,本研究还发现紫草素能够抑制甲状腺肿瘤细胞上皮间质转化及Slug,MMP-2,-9 and-14的表达,从而显著抑制细胞的迁移和侵袭。分子机制的研究还发现紫草素能够明显抑制Akt及Erk磷酸化,激活p16/Rb信号通路,并且紫草素的分子调节机制均由ROS介导完成。另外,来源于FTC133细胞的裸鼠皮下移植瘤实验结果证实紫草素在裸鼠体内仍具有良好的抑癌效果,重要的是,具有较小的细胞毒性。结论:通过本研究,我们首次揭示了紫草素在甲状腺肿瘤治疗方面具有良好的应用前景。
[Abstract]:Background: thyroid cancer is the most common malignant tumor of endocrine system. Although more than 80% of thyroid tumors are highly differentiated cancer, surgery and radioiodine therapy are the best. But thyroid tumor has the characteristics of easy recurrence, and there is a risk of progression to poorly differentiated or undifferentiated cancer. Poorly differentiated thyroid tumors are poorly treated with surgery and radiotherapy and chemotherapy, and the survival rate is very low. Therefore, it is still necessary to find safe and effective medical treatment drugs to make up for the defects of the existing treatment. Purple grass is extracted from the root of Chinese herbal medicine purple grass, which is a kind of naphthone active component. The traditional Chinese medicine is used in traditional Chinese medicine to live blood, cool blood, make small intestine, treat macula and water fire and so on. Modern medicine has found that it has many functions, such as anti - inflammatory, pathogenic microorganism, anti - platelet and anticancer. The anti-cancer effect has been confirmed in many kinds of tumors, such as rectal cancer, melanoma, leukemia, breast cancer and liver cancer. However, there is still a lack of application and research reports on the treatment of thyroid tumors. Objective: the purpose of this study was to reveal the effects of Ara on the biological behavior of thyroid tumors and to reveal the anticancer mechanism of Ara. Study design: This study were designed experiments, effects of shikonin on the detection of thyroid cancer cell proliferation, cycle and apoptosis, migration and invasion, and construct the subcutaneous tumor model in nude mice, the detection of shikonin in effect in vivo of thyroid tumor cells, and through the study of shikonin content and activity of different signal molecules in cell detection the molecular regulation of tumor signal. The results were as follows: the results of this study showed that herb can effectively inhibit the proliferation of thyroid tumor cells, and had a good time and dose dependence. Shikonin can induce cell cycle arrest and apoptosis in thyroid cancer, and apoptosis is induced by DNA damage mediated by reactive oxygen species (ROS) and activation of p53 signaling pathway. Meanwhile, it is also found that shikonin inhibits epithelial mesenchymal transition and expression of Slug, MMP-2 and -9 and-14 in thyroid cancer cells, thereby significantly inhibiting cell migration and invasion. Molecular mechanism studies also showed that shikonin inhibited Akt and Erk phosphorylation and activated p16/Rb signaling pathway, and the molecular regulatory mechanism of shikonin was mediated by ROS. In addition, the nude mice xenograft tumor derived from FTC133 cells showed that shikonin still had good antitumor effect in nude mice, and importantly, it had less cytotoxicity. Conclusion: through this study, we have revealed for the first time that it has a good prospect in the treatment of thyroid tumor.
【学位授予单位】：西安交通大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R736.1

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