Role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer
Role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer
复制标题
DOI：
10.1016/j.alcohol.2005.03.011
复制
发表时间：
2005-04-01
期刊：
影响因子：
2.3
通讯作者：
Mato, JM
中科院分区：
文献类型：
--
作者：
Lu, SC;Mato, JM
两个基因（MAT 1A和MAT 2A）编码必需酶甲硫氨酸腺苷转移酶（MAT），该酶催化S-腺苷甲硫氨酸（SAMe）的生物合成，S-腺苷甲硫氨酸是主要的甲基供体，在肝脏中是谷胱甘肽的前体。MAT 1A主要在肝脏中表达，而MAT 2A广泛分布。MAT 2A在快速生长和去分化期间在肝脏中被诱导。在人肝细胞癌（HCC）中，MAT 1A被MAT 2A取代。这在病理学上是重要的，因为MAT 2A表达与较低的SAMe水平和较快的生长相关，而外源性SAMe处理抑制生长。大鼠灌胃乙醇9周也表现出肝脏MAT表达的相对转换，SAMe水平降低，c-myc低甲基化，c-myc表达增加，DNA链断裂积累增加。酒精性肝病患者由于MAT 1A表达降低和MAT 1A编码的同工酶失活，导致肝脏MAT活性降低，最终导致SAMe生物合成降低。已在MAT 1A敲除小鼠模型中检查了慢性肝脏SAMe消耗的后果。在这种模型中，肝脏更容易受到损伤。此外，自发性脂肪性肝炎在8个月内发展，HCC在18个月内发展。越来越多的证据表明，除了作为甲基供体，SAMe控制肝细胞生长反应和死亡反应。虽然短暂的SAMe消耗是肝脏再生所必需的，但慢性肝脏SAMe消耗可能导致恶性转化。有趣的是，SAMe在正常肝细胞中是抗凋亡的，但在肝癌细胞中是促凋亡的。这应该使SAMe成为肝癌预防和治疗的有吸引力的药物。(c)2005年爱思唯尔公司All rights reserved.
Two genes (MAT1A and MAT2A) encode for the essential enzyme methionine adenosyltransferase (MAT), which catalyzes the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and, in the liver, a precursor of glutathione. MAT1A is expressed mostly in the liver, whereas MAT2A is widely distributed. MAT2A is induced in the liver during periods of rapid growth and dedifferentiation. In human hepatocellular carcinoma (HCC) MAT1A is replaced by MAT2A. This is important pathogenetically because MAT2A expression is associated with lower SAMe levels and faster growth, whereas exogenous SAMe treatment inhibits growth. Rats fed ethanol intragastrically for 9 weeks also exhibit a relative switch in hepatic MAT expression, decreased SAMe levels, hypomethylation of c-myc, increased c-myc expression, and increased DNA strand break accumulation. Patients with alcoholic liver disease have decreased hepatic MAT activity owing to both decreased MAT1A expression and inactivation of the MAT1A-encoded isoenzymes, culminating in decreased SAMe biosynthesis. Consequences of chronic hepatic SAMe depletion have been examined in the MAT1A knockout mouse model. In this model, the liver is more susceptible to injury. In addition, spontaneous steatohepatitis develops by 8 months, and HCC develops by 18 months. Accumulating evidence shows that, in addition to being a methyl donor, SAMe controls hepatocyte growth response and death response. Whereas transient SAMe depletion is necessary for the liver to regenerate, chronic hepatic SAMe depletion may lead to malignant transformation. It is interesting that SAMe is antiapoptotic in normal hepatocytes, but proapoptotic in liver cancer cells. This should make SAMe an attractive agent for both chernoprevention and treatment of HCC. (c) 2005 Elsevier Inc. All rights reserved.