| 题名 | 异常的Hepcidin-Ferroportin 信号通路促进乳腺癌的发展 |
| 作者 | 张书平 |
| 学位类别 | 博士 |
| 答辩日期 | 2013-05 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 刘思金 |
| 关键词 | 铁负荷 hepcidin-ferroportin 信号通路 乳腺癌 iron overload hepcidin-ferroportin signaling pathway breast cancer |
| 其他题名 | Deregulated hepcidin-ferroportin axis promotes breast cancer development |
| 学位专业 | 环境科学 |
| 中文摘要 | 铁负荷能够诱导诸多疾病，包括增加肿瘤发生的风险，研究表明，在多种肿瘤中均发生铁的紊乱。然而，目前有关在肿瘤发生发展过程中铁平衡如何被打破的问题仍缺乏了解，同时对调节铁平衡的hepcidin-ferroportin 信号通路发生异常的分子机制也不明确。 在本研究中，我们发现乳腺癌病人血清铁水平升高，表明病人体内存在铁负荷现象；同时，肿瘤组织中指示铁含量的ferritin 蛋白水平上升，表明肿瘤细胞内也发生铁负荷。进一步分析发现，肝脏来源和肿瘤自身来源的hepcidin 水平均升高，而乳腺肿瘤中的ferroportin 水平发生了降低，这些异常变化与病人的预后密切相关。 通过动物实验发现，抑制肝脏和肿瘤细胞自身hepcidin 的表达水平、hepcidin基因的敲除以及提高肿瘤细胞ferroportin 的表达水平均能降低乳腺肿瘤细胞中的铁水平，延缓小鼠体内肿瘤的生长。通过细胞实验发现，肝脏和肿瘤中hepcidin表达水平的升高主要是由铁、BMP6 和IL-6 水平的升高引起。此外，铁负荷显著促进BMP6 的表达，并且铁与IL-6 共同促进肿瘤细胞的生长，这些结果表明铁、BMP6 和IL-6 之间在调节hepcidin 的表达及影响肿瘤发展的过程中存在协同作用。 本研究证明了异常的hepcidin-ferroportin 信号通路通过调节乳腺肿瘤细胞内的铁平衡而影响乳腺肿瘤的发生发展过程，这将为乳腺癌的预防与治疗提供一定的科学依据。 |
| 英文摘要 | Iron overload can induce many diseases, including predisposing individuals to cancers, and many investigations showed iron disorders in multiple cancers; however, current understanding about abnormal intracellular iron homeostasis in cancer cells is still limited and the mechanisms underlying misregulated hepcidin-ferroportin axis in tumor development have not yet been elucidated. Here, we found both increased serum iron level in breast cancer patients, indicating systemic iron overload, and increased iron level in tumor tissues as reflected by tumor ferritin protein concentration. Futher studies revealed that the levels of circulating hepatic hepcidin and tumor-derived hepcidin were upregulated, while tumorous ferroportin level was downregulated, and all of these abnormal levels related to the prognosis of breast cancer patients. The inhibition of liver hepcidin expression by heparin, knockout of hepcidin in mice and knockdown of hepcidin expression in breast cancer cells decreased iron concentration of tumor cells and attenuated the growth of tumors in mice. Meanwhile,forced expression of ferroportin constructs also inhibited the growth of tumors in mice. Increased iron burden and BMP6 and IL-6 concentrations were responsible for increased hepatic hepcidin and tumorous hepcidin expression. Excessive iron greatly induced BMP6 synthesis, and iron/IL-6 enhanced tumor cells’ survival, which indicating that iron, BMP6 and IL-6 synergistically drived hepcidin expression and regulated tumor development. Our findings identified a crucial role of the hepcidin-ferroportin axis in governing tumor development through iron metabolism. Therapeutics that target different aspects of iron metabolism would open new avenue for the prevention and treatment of breast cancers in the future. |
| 公开日期 | 2014-10-28 |
| 内容类型 | 学位论文 |
| 源URL | [http://ir.rcees.ac.cn/handle/311016/7702]  |
| 专题 | 生态环境研究中心_环境化学与生态毒理学国家重点实验室 |
| 推荐引用方式 GB/T 7714 | 张书平. 异常的Hepcidin-Ferroportin 信号通路促进乳腺癌的发展[D]. 北京. 中国科学院研究生院. 2013. |
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