Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells
Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells
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DOI：
10.1093/carcin/bgi312
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发表时间：
2006-05-01
期刊：
影响因子：
4.7
通讯作者：
Kim, YI
中科院分区：
文献类型：
--
作者：
Novakovic, P;Stempak, JM;Kim, YI
叶酸是一种 B 族维生素，缺乏叶酸似乎会增加患多种恶性肿瘤（包括结直肠癌）的风险。与正常组织中叶酸缺乏的促癌作用相反，多项证据表明叶酸缺乏可抑制现有肿瘤的进展并增强癌细胞对化疗的敏感性。叶酸介导嘌呤和胸苷酸从头生物合成所需的一碳转移，因此是 DNA 合成和修复以及维持 DNA 完整性和稳定性的重要因素。叶酸缺乏会导致 DNA 链断裂、增加尿嘧啶错误掺入 DNA、损害 DNA 修复并似乎诱导细胞凋亡。尽管叶酸缺乏对 DNA 完整性和细胞凋亡以及随后的结肠上皮细胞癌症发生、进展和治疗的影响已得到充分表征，但目前尚不清楚叶酸缺乏如何调节细胞凋亡和调节这些过程的癌症途径中的特定上游基因。因此，我们在叶酸缺乏的体外模型中研究了叶酸缺乏对四种人结肠腺癌细胞系中参与细胞凋亡和癌症途径的基因表达的影响。使用细胞凋亡和癌症途径特异性微型微阵列来筛选响应叶酸缺乏的差异表达基因，并通过实时 RT-PCR 证实了七个最显着且一致受影响的基因的表达。我们的数据表明，叶酸缺乏以细胞特异性方式影响与细胞周期控制、DNA 修复、细胞凋亡和血管生成相关的关键基因的表达。叶酸缺乏导致的基因表达变化的细胞特异性可能是由于四种细胞系之间分子和表型特征、生长速率和细胞内叶酸浓度的显着差异。
Folate is a B vitamin, deficiency of which appears to increase the risk of developing several malignancies including colorectal cancer. In contrast to the cancer-promoting effect of folate deficiency in normal tissues, several lines of evidence indicate that folate depletion suppresses the progression of existing neoplasms and enhance the sensitivity of cancer cells to chemotherapy. Folate mediates the transfer of one-carbon necessary for the de novo biosynthesis of purines and thymidylate, and hence is an essential factor for DNA synthesis and repair, and the maintenance of DNA integrity and stability. Folate deficiency induces DNA strand breaks, increases uracil misincorporation into DNA, impairs DNA repair and appears to induce apoptosis. Although the effects of folate depletion on DNA integrity and apoptosis and on subsequent cancer development, progression and treatment in colonic epithelial cells have been well characterized, it is largely unknown at present how folate depletion modulates specific upstream genes in apoptosis and cancer pathways that regulate these processes. We therefore investigated the effects of folate depletion on expression of genes involved in apoptosis and cancer pathways in four human colon adenocarcinoma cell lines in an in vitro model of folate deficiency. Apoptosis and cancer pathway-specific mini-microarray were used to screen for differentially expressed genes in response to folate deficiency, and the expression of seven most notably and consistently affected genes was confirmed by real time RT-PCR. Our data suggest that folate deficiency affects the expression of key genes that are related to cell cycle control, DNA repair, apoptosis and angiogenesis in a cell-specific manner. Cell-specificity in gene expression changes in response to folate deficiency is likely due to significant differences in molecular and phenotypic characteristics, growth rates and intracellular folate concentrations among the four cell lines.