Kim Young-In
Departments of Medicine and Nutritional Sciences, University of Toronto, Medical Sciences Building Room 7258, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Cancer Epidemiol Biomarkers Prev. 2004 Apr;13(4):511-9.
Epidemiological, clinical, and animal studies collectively indicate that dietary folate intake and blood folate levels are inversely associated with colorectal cancer risk. Folate plays an essential role in one-carbon transfer involving remethylation of homocysteine to methionine, which is a precursor of S-adenosylmethionine, the primary methyl group donor for most biological methylations. DNA methylation is an important epigenetic determinant in gene expression, maintenance of DNA integrity and stability, chromosomal modifications, and development of mutations. Dysregulation and aberrant patterns of DNA methylation are generally considered to be mechanistically involved in colorectal carcinogenesis. Aberrant DNA methylation has been considered as a leading mechanism by which folate deficiency enhances colorectal carcinogenesis. However, currently available data pertaining to the effects of folate deficiency on DNA methylation are inconsistent and incomplete. The portfolio of evidence from animal, human, and in vitro studies suggests that the effects of folate deficiency on DNA methylation are highly complex; appear to depend on cell type, target organ, and stage of transformation; and are gene and site specific. In addition, the pattern of site- and gene-specific DNA methylation induced by folate deficiency may not be in concert with the direction of changes in genomic DNA methylation. Collectively, currently available evidence indicates that genomic DNA hypomethylation in the colorectum is not a probable mechanism by which folate deficiency enhances colorectal carcinogenesis. However, there is still a possibility that sequence-specific alterations of DNA methylation in critical cancer-related genes might be mechanistically involved in the folate deficiency-mediated colorectal carcinogenesis.
流行病学、临床和动物研究共同表明，膳食叶酸摄入量和血液叶酸水平与结直肠癌风险呈负相关。叶酸在一碳转移中起着至关重要的作用，该过程涉及将同型半胱氨酸重新甲基化为甲硫氨酸，甲硫氨酸是S-腺苷甲硫氨酸的前体，而S-腺苷甲硫氨酸是大多数生物甲基化的主要甲基供体。DNA甲基化是基因表达、DNA完整性和稳定性维持、染色体修饰以及突变发生过程中的一个重要表观遗传决定因素。DNA甲基化的失调和异常模式通常被认为在结直肠癌发生机制中起作用。异常DNA甲基化被认为是叶酸缺乏增强结直肠癌发生的主要机制。然而，目前关于叶酸缺乏对DNA甲基化影响的数据并不一致且不完整。来自动物、人体和体外研究的证据表明，叶酸缺乏对DNA甲基化的影响非常复杂；似乎取决于细胞类型、靶器官和转化阶段；并且具有基因和位点特异性。此外，叶酸缺乏诱导的位点和基因特异性DNA甲基化模式可能与基因组DNA甲基化变化的方向不一致。总体而言，目前可得的证据表明，结肠直肠中的基因组DNA低甲基化不是叶酸缺乏增强结直肠癌发生的可能机制。然而，关键癌症相关基因中DNA甲基化的序列特异性改变仍有可能在叶酸缺乏介导的结直肠癌发生机制中起作用。
