亚砷酸钠血管效应及诱导EMT作用研究
发布时间：2018-11-17 14:53
【摘要】：目前,全世界大约有数亿人暴露在高砷环境中,中国是受砷危害的最为严重的国家之一,地方性砷中毒在我国发现时间短、病情重、病区范围大,而且暴露在高砷水平下的人口还在继续扩大。 由于砷在体内作用机制复杂,其慢性毒性作用及致病机理仍然不是很清楚,对砷的发病机理研究至今仍没有取得突破性的进展,近几年研究表明,砷中毒主要导致血管病变,特别是对血管内皮的损伤。血管内皮是覆盖在血管内膜表层,在血管损伤的自我修复过程中起决定作用。目前研究已确切表明,地砷病不但可以造成各系统疾病,长期接触砷,还可导致各种癌症,如膀胱癌、肺癌、肝癌、乳腺癌等。迄今为止,砷的致癌机制仍不清楚。基于以上原因我们应用鸡胚绒毛尿囊膜(CAM)血管新生模型作为亚砷酸钠对血管增殖影响体内研究模型；以人脐静脉内皮细胞(HUV-EC)作为亚砷酸钠对血管增殖的体外研究模型,观察亚砷酸钠对血管增殖毒性效应；以小鼠乳腺上皮细胞(NMuMG)为研究对象,研究砷的诱导EMT作用,以期为砷的致癌机制提供理论依据。经研究我们发现,NaAsO2对体内外血管增殖均有抑制作用,这可能是砷化物中毒引起血管疾病的发生机制之一。在应用小鼠乳腺上皮细胞(NMuMG)作为研究砷诱导EMT模型之前,我们先观察了砷对NMuMG的直接毒性效应。我们首次发现NaAsO2能够改变细胞形态,抑制细胞增殖,引起细胞凋亡,且通过抑制c-Myc表达,促进P21表达来实现的。为了研究砷诱导EMT,我们先建立了TGF-β介导的EMT模型,接着我们首次成功的通过NaAsO2介导NMuMG发生EMT,同时我们还进一步发现砷是通过HMGA2途径诱导EMT。 上述研究结果为地砷病的血管损伤机制提供了进一步的理论依据,同时对于砷的致癌机制提供新的理论基础,砷正是通过引起正常细胞的发生上皮向间充质细胞的转化而引起癌症的。
[Abstract]:At present, there are hundreds of millions of people in the world exposed to high arsenic environment. China is one of the countries most seriously affected by arsenic. Endemic arsenic poisoning is found in China for a short time, the disease is serious, and the scope of the disease area is large. And the population exposed to high arsenic levels continues to grow. Because of the complex mechanism of arsenic acting in vivo, the chronic toxicity and pathogenesis of arsenic are still unclear. So far, no breakthrough has been made in the study of the pathogenesis of arsenic. In recent years, it has been shown that arsenic poisoning mainly leads to vascular disease. Especially the injury of vascular endothelium. Vascular endothelium is covered in the intimal layer and plays a decisive role in the self-repair of vascular injury. At present, it has been proved that the disease can not only cause systemic diseases, long-term exposure to arsenic, but also lead to various cancers, such as bladder cancer, lung cancer, liver cancer, breast cancer and so on. To date, the carcinogenic mechanism of arsenic remains unclear. For the above reasons, we used the chicken chorioallantoic membrane (CAM) angiogenesis model as an in vivo model to study the effect of sodium arsenite on vascular proliferation. Human umbilical vein endothelial cells (HUV-EC) were used as an in vitro model to study the effects of sodium arsenite on the proliferation of blood vessels. In order to provide theoretical basis for the carcinogenic mechanism of arsenic, the EMT induced by arsenic in mouse mammary epithelial cells (NMuMG) was studied. We found that NaAsO2 can inhibit the proliferation of blood vessels in vivo and in vitro, which may be one of the mechanisms of vascular diseases caused by arsenide poisoning. Before using mouse mammary epithelial cell (NMuMG) as the model of arsenic induced EMT, we observed the direct toxicity of arsenic to NMuMG. We found for the first time that NaAsO2 could change cell morphology, inhibit cell proliferation and induce apoptosis, which was achieved by inhibiting the expression of c-Myc and promoting the expression of P21. In order to study arsenic induced EMT, we first established TGF- 尾 -mediated EMT model, then we successfully induced NMuMG EMT, by NaAsO2 for the first time, and we further found that arsenic induces EMT. via HMGA2 pathway. These results provide a further theoretical basis for the vascular injury mechanism of arsenic disease, and provide a new theoretical basis for the carcinogenesis mechanism of arsenic. Arsenic causes cancer by causing the transformation of normal cells from epithelium to mesenchymal cells.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R363
本文编号：2338180
[Abstract]:At present, there are hundreds of millions of people in the world exposed to high arsenic environment. China is one of the countries most seriously affected by arsenic. Endemic arsenic poisoning is found in China for a short time, the disease is serious, and the scope of the disease area is large. And the population exposed to high arsenic levels continues to grow. Because of the complex mechanism of arsenic acting in vivo, the chronic toxicity and pathogenesis of arsenic are still unclear. So far, no breakthrough has been made in the study of the pathogenesis of arsenic. In recent years, it has been shown that arsenic poisoning mainly leads to vascular disease. Especially the injury of vascular endothelium. Vascular endothelium is covered in the intimal layer and plays a decisive role in the self-repair of vascular injury. At present, it has been proved that the disease can not only cause systemic diseases, long-term exposure to arsenic, but also lead to various cancers, such as bladder cancer, lung cancer, liver cancer, breast cancer and so on. To date, the carcinogenic mechanism of arsenic remains unclear. For the above reasons, we used the chicken chorioallantoic membrane (CAM) angiogenesis model as an in vivo model to study the effect of sodium arsenite on vascular proliferation. Human umbilical vein endothelial cells (HUV-EC) were used as an in vitro model to study the effects of sodium arsenite on the proliferation of blood vessels. In order to provide theoretical basis for the carcinogenic mechanism of arsenic, the EMT induced by arsenic in mouse mammary epithelial cells (NMuMG) was studied. We found that NaAsO2 can inhibit the proliferation of blood vessels in vivo and in vitro, which may be one of the mechanisms of vascular diseases caused by arsenide poisoning. Before using mouse mammary epithelial cell (NMuMG) as the model of arsenic induced EMT, we observed the direct toxicity of arsenic to NMuMG. We found for the first time that NaAsO2 could change cell morphology, inhibit cell proliferation and induce apoptosis, which was achieved by inhibiting the expression of c-Myc and promoting the expression of P21. In order to study arsenic induced EMT, we first established TGF- 尾 -mediated EMT model, then we successfully induced NMuMG EMT, by NaAsO2 for the first time, and we further found that arsenic induces EMT. via HMGA2 pathway. These results provide a further theoretical basis for the vascular injury mechanism of arsenic disease, and provide a new theoretical basis for the carcinogenesis mechanism of arsenic. Arsenic causes cancer by causing the transformation of normal cells from epithelium to mesenchymal cells.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R363
【参考文献】
相关期刊论文 前2条
1 张旭;于秀敏;谢亲建;李红玉;;砷的微生物转化及其在环境与医学应用中的研究进展[J];微生物学报;2008年03期
2 孙永琨;王书杰;赵永强;;五氧化二砷对人脐静脉内皮细胞增殖和凋亡的影响[J];中国医学科学院学报;2009年05期
，本文编号：2338180
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