Top Institute Food and Nutrition, Wageningen, The Netherlands.
Gut. 2012 Jul;61(7):1041-9. doi: 10.1136/gutjnl-2011-300239. Epub 2011 Sep 24.
Colon cancer is a leading cause of cancer deaths in Western countries and is associated with diets high in red meat. Haem, the iron-porphyrin pigment of red meat, induces cytotoxicity of gut contents and damages the colon surface epithelium. Compensatory hyperproliferation leads to epithelial hyperplasia which increases the risk of colon cancer. The aim of this study was to identify molecules signalling from the surface epithelium to the crypt to initiate hyperproliferation upon stress induced by haem.
C57Bl6/J mice (n=9/group) received a 'westernised' control diet (40 en% fat) with or without 0.5 μmol/g haem for 14 days. Colon mucosa was used to quantify cell proliferation and for microarray transcriptome analysis. Gene expression profiles of surface and crypt cells were compared using laser capture microdissection. Protein levels of potential signalling molecules were quantified.
Haem-fed mice showed epithelial hyperproliferation and decreased apoptosis, resulting in hyperplasia. Microarray analysis of the colon mucosa showed 3710 differentially expressed genes (false discovery rate (q) <0.01), with many involved in the cell cycle. Expression levels of haem- and stress-related genes showed that haem affected surface cells but did not directly affect crypt cells. Injured surface cells should therefore signal to crypt cells to induce compensatory hyperproliferation. Haem downregulated the inhibitors of proliferation, Wnt inhibitory factor 1, Indian Hedgehog and bone morphogenetic protein 2. Interleukin-15 was also downregulated. Haem upregulated amphiregulin, epiregulin and cyclo-oxygenase-2 mRNA in surface cells. Their protein/metabolite levels were, however, not increased as haem induced surface-specific inhibition of translation by increasing 4E-BP1.
Haem induces colonic hyperproliferation and hyperplasia by inhibiting the surface to crypt signalling of feedback inhibitors of proliferation.
结肠癌是西方国家癌症死亡的主要原因，与高红肉饮食有关。血红素是红肉中铁卟啉色素，它诱导肠道内容物的细胞毒性，并损害结肠表面上皮。代偿性增殖导致上皮增生，增加结肠癌的风险。本研究的目的是确定从表面上皮向隐窝发出信号的分子，以在血红素诱导的应激下启动增殖。
C57Bl6/J 小鼠（每组 9 只）接受“西式”对照饮食（40%脂肪），或加或不加 0.5μmol/g 血红素，喂养 14 天。用结肠黏膜定量细胞增殖和进行微阵列转录组分析。使用激光捕获显微切割比较表面和隐窝细胞的基因表达谱。定量潜在信号分子的蛋白水平。
血红素喂养的小鼠表现出上皮细胞过度增殖和凋亡减少，导致增生。结肠黏膜的微阵列分析显示 3710 个差异表达基因（错误发现率（q）<0.01），其中许多与细胞周期有关。血红素和应激相关基因的表达水平表明，血红素影响表面细胞，但不直接影响隐窝细胞。因此，受损的表面细胞应该向隐窝细胞发出信号，以诱导代偿性增殖。血红素下调增殖抑制剂 Wnt 抑制因子 1、印度刺猬因子和骨形态发生蛋白 2。白细胞介素-15 也下调。血红素在上皮细胞中上调了 Amphiregulin、Epiregulin 和环氧化酶-2mRNA。然而，由于血红素通过增加 4E-BP1 来抑制表面翻译，因此没有增加其蛋白/代谢物水平。
血红素通过抑制增殖反馈抑制剂的表面到隐窝信号，诱导结肠过度增殖和增生。
