Ren Feng, Li Jian, Wang Yanglin, Wang Yongxia, Feng Sijia, Yuan Zhiqing, Qian Xinlai
Department of Pathology, Xinxiang Medical University, Xinxiang, China.
Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.
Cell Physiol Biochem. 2018;47(3):1084-1094. doi: 10.1159/000490185. Epub 2018 May 25.
BACKGROUND/AIMS: Iron plays a fundamental role in cell biology and its concentration must be precisely regulated. It is well documented that excess iron burden contributes to the occurrence and progression of cancer. Hepcidin secreted by liver plays an essential role in orchestrating iron metabolism. In the present study, we aimed to investigate the ability of angelica sinensis polysaccharide (ASP) to decrease iron burden in tumor-bearing mice and the mechanism of ASP regulation hepcidin expression.
Western blot, RT-PCR, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA) were used to detect the regulation of hepcidin and related cytokines by ASP. The role of ASP in tumor proliferation was investigated using in vivo assays. Iron depositions and iron concentrations in organs were determined by hematoxylin-eosin (H&E) staining and atomic absorption spectrophotometer.
We found that ASP could inhibit tumor growth in mice xenografted with 4T1 and H22 cancer cells. In vivo experiments also showed that ASP could potently regulate hepcidin expression in liver and serum and decrease iron burden in liver, spleen and grafted tumors in mouse model. Treatment with ASP in hepatic cell lines reproduced comparable results in decreasing hepcidin as in mouse liver. Furthermore, we found that ASP markedly suppressed the expression of interleukin-6 (IL-6), JAK2, p-STAT3, and p-SMAD1/5/8 in liver, suggesting that JAK/STAT and BMP-SMAD pathways were involved in the regulation of hepcidin expression by ASP. We also found down-regulation of iron-related cytokines in ASP treated mice.
The present study provides new evidence that ASP decreases hepcidin expression, which can reduce iron burden and inhibit tumor proliferation. These findings might aid ASP developed as a potential candidate for cancer treatment in patients with iron overload.
背景/目的：铁在细胞生物学中起着重要作用，其浓度必须得到精确调节。有充分的文献记载，铁负荷过重会促进癌症的发生和发展。肝脏分泌的铁调素在协调铁代谢中起着至关重要的作用。在本研究中，我们旨在探讨当归多糖（ASP）降低荷瘤小鼠铁负荷的能力以及ASP调节铁调素表达的机制。
采用蛋白质免疫印迹法、逆转录-聚合酶链反应、免疫组织化学和酶联免疫吸附测定法检测ASP对铁调素及相关细胞因子的调节作用。通过体内实验研究ASP在肿瘤增殖中的作用。采用苏木精-伊红染色和原子吸收分光光度计测定器官中的铁沉积和铁浓度。
我们发现ASP可以抑制4T1和H22癌细胞异种移植小鼠的肿瘤生长。体内实验还表明，ASP可以有效调节小鼠模型肝脏和血清中铁调素的表达，并降低肝脏、脾脏和移植瘤中的铁负荷。在肝细胞系中用ASP处理可产生与小鼠肝脏中降低铁调素相当的结果。此外，我们发现ASP显著抑制肝脏中白细胞介素-6（IL-6）、JAK2、p-STAT3和p-SMAD1/5/8的表达，提示JAK/STAT和BMP-SMAD信号通路参与了ASP对铁调素表达的调节。我们还发现ASP处理的小鼠中铁相关细胞因子下调。
本研究提供了新的证据，表明ASP降低铁调素表达，从而减轻铁负荷并抑制肿瘤增殖。这些发现可能有助于将ASP开发成为铁过载患者癌症治疗的潜在候选药物。
