缺氧诱导因子2alpha在高铁饮食促进的结直肠癌发病中作用的研究

Despite a close association between excess dietary iron and colorectal cancer (CRC), the molecular link between excess dietary iron and CRC has not been fully uncovered. We and others found that excess iron deposits in colorectal tumor regions but not normal colon tissues, suggesting that abnormal iron metabolism exists in CRC. We previously demonstrate that intestinal hypoxia-inducible factor 2alpha(HIF2alpha) but not HIF1alpha serves as a crucial transcription factor in controlling intestinal iron absorption via directly targeting iron absorptive genes Dmt1 (divalent mental transporter-1), DcytB (duodenal cytochrome b) and Fpn (ferroportin). Using transgenic mouse model with intestinal-specific HIF2alpha overexpression, we found that HIF2alpha activation accelerates colorectal tumorigenesis and progression. Of particular interest, our preliminary study showed that DMT1, a HIF2alpha direct target essential for iron absorption in intestine, is highly expressed in colorectal tumors, consistent with the pattern of HIF2alpha expression and iron deposition in CRC. Therefore, we hypothesized that HIF2alpha may act as a molecular link between excess dietary iron and CRC. We plan to investigate the mechanisms by which intestinal HIF2alpha is activated by excess dietary iron and whether HIF2alpha inhibition retards excess dietary iron-accelerated CRC using established transgenic models and cell lines. The research will provide novel potential targets and strategies for therapeutics of CRC.

尽管流行病学显示高铁饮食与结直肠癌（CRC）发生密切相关，但机制不明确。研究发现，CRC局部过量铁沉积，提示局部铁代谢紊乱。我们证实，缺氧诱导因子2a（HIF2a）通过靶基因DcytB、DMT1和FPN控制肠道铁吸收，是调节肠道铁吸收的关键转录因子。利用组织特异性基因敲除鼠，我们发现肠上皮HIF2a激活可明显促进CRC发生和恶性转化。预实验结果还显示，HIF2a的直接靶基因DMT1在CRC局部异常高表达，其模式与过量铁沉积和HIF2a在CRC的表达模式（仅表达于肿瘤而非正常组织）相似。因此，本项目提出假说：HIF2a可作为高铁饮食与CRC之间的联系纽带，介导过量铁沉积和加速CRC进程。本项目拟在遗传突变诱导的CRC模型Apcmin/+中从局部铁代谢异常角度深入探讨高铁饮食激活HIF2a以及促进CRC的机制，对搞清CRC发病的饮食源性机制、寻找防治CRC的新靶点具重要理论意义和潜在应用价值。