Folate status: Effects on pathways of colorectal carcinogenesis
Folate status: Effects on pathways of colorectal carcinogenesis
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DOI：
10.1093/jn/132.8.2413s
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发表时间：
2002-08-01
影响因子：
4.2
通讯作者：
Mason, JB
中科院分区：
文献类型：
--
作者：
Choi, SW;Mason, JB
许多流行病学、动物和人类研究表明，叶酸状态调节癌症的发生。虽然这些观察已经在许多组织中进行，但这些数据显然对结直肠最有说服力。这种调节的机制(S)仍然不清楚。基因组范围或基因特异性DNA甲基化的改变和/或DNA稳定性的改变是这方面的主要候选因素，这些改变是由DNA链断裂或尿嘧啶错误结合引起的。叶酸在生物甲基化和核苷酸合成中起着核心作用，因此，观察到叶酸枯竭会改变DNA甲基化并降低DNA的稳定性也就不足为奇了。这两条途径是叶酸调节癌症风险的途径这一假说也得到了流行病学观察的支持，即亚甲基四氢叶酸还原酶(MTHFR；EC 1.5.1.20)基因的常见多态对结肠癌的相对风险产生不同的影响，这取决于叶酸状态，因为MTHFR催化决定细胞叶酸是被转移到生物甲基化还是核苷酸合成的反应。这一现象表明，是生物甲基化和核苷酸合成之间的失衡导致了叶酸相关癌症的发生。控制细胞增殖，这也与DNA甲基化有关，是叶酸状态调节癌症发生的另一个候选机制。在细胞培养研究中，已观察到补充叶酸可以抑制细胞过度增殖。了解叶酸状态调节癌症发生的机制对于促进对癌症生物学的洞察和促进将叶酸和癌症发生的研究转化为有效和安全的公共卫生倡议具有重要意义。
Many epidemiologic, animal and human studies suggest that folate status modulates carcinogenesis. Although these observations have been made in a number of tissues, the data are clearly most compelling for the colorectum. The mechanism(s) by which this modulation is mediated remains ill defined. Alterations in either genome-wide or gene-specific DNA methylation and/or alterations in DNA stability, resulting from DNA strand breaks or uracil misincorporation, are leading candidates in this regard. Folate has a central role in biological methylation and nucleotide synthesis, and therefore it is not surprising that folate depletion has been observed to alter DNA methylation and diminish DNA stability. The hypothesis that these two pathways are the means by which folate modulates cancer risk is also supported by the epidemiological observation that a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) gene differentially affects the relative risk of colon cancer depending on folate status, because MTHFR catalyzes the reaction that determines whether cellular folate is diverted into biological methylation or nucleotide synthesis. This phenomenon suggests that it is an imbalance between biological methylation and nucleotide synthesis that is responsible for folate-related carcinogenesis. The control of cell proliferation, which also is related to DNA methylation, is another candidate mechanism by which folate status modulates carcinogenesis. In cell culture studies, folate supplementation has been observed to suppress excessive cell proliferation. Understanding the mechanisms by which folate status modulates carcinogenesis is important for advancing insight into cancer biology and for facilitating those efforts to translate research in folate and carcinogenesis into effective and safe public health initiatives.