Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines
Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines
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DOI：
10.1016/j.jnutbio.2007.05.003
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发表时间：
2008-05-01
影响因子：
5.6
通讯作者：
Mason, Joel B.
中科院分区：
文献类型：
--
作者：
Crott, Jimmy W.;Liu, Zhenhua;Mason, Joel B.
叶酸缺乏可通过破坏DNA甲基化模式或通过诱导碱基取代、DNA断裂、基因缺失和基因扩增来影响基因表达。表达的变化可以解释叶酸状态和结直肠癌风险之间的负相关关系。来自正常人结肠的三种细胞系HCEC、NCM 356和NCM 460在含有25、50、75或150 nM叶酸的培养基中生长32-34天，并测定涉及细胞周期检查点、细胞内信号传导、叶酸摄取和细胞粘附和迁移的基因的表达。叶酸受体I的表达随着所有细胞系中培养基叶酸的减少而增加，p53、p21、p16和β-连环蛋白也是如此。随着叶酸水平的降低，NCM 356中E-钙粘蛋白和SMAD-4的表达均降低。APC在NCM 356中升高，但在其他系中不变。未检测到整体甲基化的变化。在NCM 460细胞中，随着叶酸的减少，观察到p53外显子7-8链断裂显著增加。观察到的变化与DNA损伤诱导的细胞周期检查点激活和细胞对叶酸消耗的适应一致。叶酸耗竭诱导的Wnt/APC途径以及参与细胞粘附、迁移和侵袭的基因的变化可能是叶酸状态与癌症风险之间观察到的关系的基础。(c)2008年爱思唯尔公司All rights reserved.
Folate deficiency may affect gene expression by disrupting DNA methylation patterns or by inducing base substitution, DNA breaks, gene deletions and gene amplification. Changes in expression may explain the inverse relationship observed between folate status and risk of colorectal cancer. Three cell lines derived from the normal human colon, HCEC, NCM356 and NCM460, were grown for 32-34 days in media containing 25, 50, 75 or 150 nM folic acid, and the expression of genes involved in cell-cycle checkpoints, intracellular signaling, folate uptake and cell adhesion and migration was determined. Expression of Folate Receptor I was increased with decreasing media folate in all cell lines, as was p53, p21, p16 and beta-catenin. With decreasing folate, the expression of both E-cadherin and SMAD-4 was decreased in NCM356. APC was elevated in NCM356 but unchanged in the other lines. No changes in global methylation were detected. A significant increase in p53 exon 7-8 strand breaks was observed with decreasing folate in NCM460 cells. The changes observed are consistent with DNA damage-induced activation of cell-cycle checkpoints and cellular adaptation to folate depletion. Folate-depletion-induced changes in the Wnt/APC pathway as well as in genes involved in cell adhesion, migration and invasion may underlie observed relationships between folate status and cancer risk. (c) 2008 Elsevier Inc. All rights reserved.