Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis
Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis
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DOI：
10.1038/onc.2009.332
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发表时间：
2010-01-21
期刊：
影响因子：
8
通讯作者：
Jin, H. C.
中科院分区：
文献类型：
--
作者：
Liu, X.;Wang, X.;Jin, H. C.
在癌细胞中，葡萄糖通常转化为乳酸，这被称为“瓦尔堡效应”。癌细胞具有较高的有氧糖酵解速率而不是氧化磷酸化速率的原因在很大程度上仍然不清楚。在此，我们提出了瓦尔堡效应的表观遗传机制。在Ras转化的NIH 3 T3细胞中，具有拮抗糖酵解功能的果糖-1，6-二磷酸酶-1（FBP 1）通过NF-κ B途径下调。FBP 1表达的恢复抑制了锚定非依赖性生长，表明FBP 1下调在癌发生中的相关性。FBP 1在胃癌（P < 0.01，n = 22）和胃癌细胞系（57%，4/7）中表达下调。FBP 1表达的恢复减少了胃癌细胞的生长和糖酵解。此外，药物去甲基化可逆转FBP 1下调。胃癌细胞株和胃癌组织中其启动子甲基化率分别为57%（4/7）和33%（33/101）。抑制NF-κ B恢复FBP 1的表达，部分通过FBP 1启动子的去甲基化。值得注意的是，考克斯回归分析显示FBP 1启动子甲基化是胃癌的独立预后预测因子（风险比：3.60，P = 0.010）。总之，我们发现NF-kappaB在Ras下游发挥作用，促进FBP 1的表观遗传下调。FBP 1基因启动子甲基化可作为胃癌预后预测的一个新的生物标志物。糖酵解和癌症发生之间如此重要的表观遗传联系部分解释了瓦尔堡效应。Oncogene（2010）29，442-450; doi：10.1038/onc.2009.332; 2009年11月2日在线发表
In cancer cells, glucose is often converted into lactic acid, which is known as the 'Warburg effect'. The reason that cancer cells have a higher rate of aerobic glycolysis, but not oxidative phosphorylation, remains largely unclear. Herein, we proposed an epigenetic mechanism of the Warburg effect. Fructose-1,6-bisphosphatase-1 (FBP1), which functions to antagonize glycolysis was downregulated through NF-kappaB pathway in Ras-transformed NIH3T3 cells. Restoration of FBP1 expression suppressed anchorage-independent growth, indicating the relevance of FBP1 downregulation in carcinogenesis. Indeed, FBP1 was downregulated in gastric carcinomas (P < 0.01, n = 22) and gastric cancer cell lines (57%, 4/7). Restoration of FBP1 expression reduced growth and glycolysis in gastric cancer cells. Moreover, FBP1 downregulation was reversed by pharmacological demethylation. Its promoter was hypermethylated in gastric cancer cell lines (57%, 4/7) and gastric carcinomas (33%, 33/101). Inhibition of NF-kappaB restored FBP1 expression, partially through demethylation of FBP1 promoter. Notably, Cox regression analysis revealed FBP1 promoter methylation as an independent prognosis predicator for gastric cancer (hazard ratio: 3.60, P = 0.010). In summary, we found that NF-kappaB functions downstream of Ras to promote epigenetic downregulation of FBP1. Promoter methylation of FBP1 can be used as a new biomarker for prognosis prediction of gastric cancer. Such an important epigenetic link between glycolysis and carcinogenesis partly explains the Warburg effect. Oncogene (2010) 29, 442-450; doi:10.1038/onc.2009.332; published online 2 November 2009