文章快速检索    
甲硫氨酸腺苷转移酶1A/2A平衡与肝细胞癌
李子涵1** , 熊婷1,2** , 熊晓丽1 , 卢子贤1 , 周志刚3 , 涂剑1     
1. 南华大学药物药理研究所,衡阳 421001;
2. 长沙医学院,长沙 410219;
3. 长南华大学附属第一医院,衡阳 421001
摘要: 肝细胞癌是一种死亡率极高的癌症,大多数病人发现时已属晚期.甲硫氨酸腺苷转移酶(MAT)是细胞生命活动的关键酶,可以通过催化甲酼氨酸和三磷酸腺苷(ATP)结合,促进生物甲基供体S-腺苷甲酼氨酸(SAMe)的生物合成.正常肝细胞中MAT1A与MAT2A存在动态平衡,共同维持细胞内SAMe稳态;肝细胞癌中MAT1A转变成MAT2A,会使SAMe生物合成减少,为癌细胞生长提供有利条件,故MAT1A表达降低而MAT2A增高.因此,促进MAT2A向MAT1A转化,进而提高MAT1A/MAT2A的比值可能成为治疗肝细胞癌的关键靶点之一.本文就MAT1A/MAT2A平衡在肝细胞癌中的重要作用作一综述,旨在为寻找肝细胞癌防治靶点提供新的思路.
关键词: 甲硫氨酸腺苷转移酶1A     甲硫氨酸腺苷转移酶2A     肝细胞癌     平衡调控    
Equilibrium of Methionine Adenosine Transferase 1A / 2A and Hepatocellular Carcinoma
LI Zi-Han1** , XIONG Ting1,2** , XIONG Xiao-Li1 , LU Zi-Xian1 , ZHOU Zhi-Gang3 , TU Jian1     
1. Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China;
2. Changsha Medical University, Changsha 410219, China;
3. The First Affiliated Hospital, University of South China, Hengyang 421001, China
*This work was supported by grants from The National Natural Science Foundation of China (81541163), the Open Fund Based on Innovation Platform of Hunan Provincial Education Department (15 K111), High-leveltalent research start-up fund of University of South China in 2017 (24) and Hunan Provincial Cooperative Innovation Center for Molecular Target New Drug Study (2016-429)
**These authors contributed equally to this work
*** Corresponding author: Tel: 0734-8281782 ZHOU Zhi-Gang. E-mail: zhouzhigang0734@sina.com
TU Jian. E-mail: tujian0734@aliyun.com
Received: May 5, 2018 Accepted: June 21, 2018
Abstract: Hepatocellular carcinoma (HCC) is a kind of cancer with extremely high mortality. Most patients have been in the advanced stage when they went to see the doctor. The enzyme methionine adenosine transferase (MAT), as the key to the survival of the cell, could promote the biosynthesis of the biological methyl donor S-adenosylmethionine (SAMe) by catalyzing the binding of methionine and adenosine triphosphate (ATP). There is a dynamic equilibrium between MAT1A and MAT2A in normal hepatocytes, which maintains the homeostasis of SAMe. The transformation of MAT1A to MAT2A will reduce the biosynthesis of SAMe and provide favorable conditions for the cell growth of HCC. Generally speaking, MAT1A expression is high but MAT2A expression is low in healthy liver tissues while MAT1A is decreased but MAT2A increased in HCC. Therefore, to accelerate the transformation of MAT2A to MAT1A, then improve the MAT1A/MAT2A ratio would be as a key to HCC treatment. This article mainly discusses the transformation of MAT1A to MAT2A in HCC, aiming to find a new way to explore the target for HCC prevention and treatment.
Key words: methionine adenosine transferase 1A     methionine adenosine transferase 2A     hepatocellular carcinoma (HCC)     balance control    

原发性肝癌包括肝细胞癌、胆管细胞型肝癌和混合型肝癌等[1].其中肝细胞癌是一种死亡率极高的癌症,特别是在受肝炎病毒影响严重的亚洲地区.大多数病人发现时已属晚期,失去手术机会,并将面临术后易复发转移等问题.文献报道[2-4],当肝功能障碍时,甲硫氨酸腺苷转移酶(methionine adenosyltransferase,MAT)失活,影响S-腺苷甲硫氨酸(S-adenosylmethionine,AdoMet,SAMe或SAM)等基因异常表达,在肝细胞恶性转变的过程中起关键作用.

在哺乳动物肝脏中,MAT家族主要有MAT1A、MAT2A和MAT2B三种.其中MAT1A具有肝脏特异性,是肝细胞高分化的标志,可促进SAMe合成;而MAT2A则抑制SAMe的合成[5].最近的文献提示[6],正常肝组织中未见表达的MAT2B在肝癌组织中的表达阳性率明显高于癌旁组织,但尚需进一步的文献证实.故正常肝细胞中主要存在MAT1A与MAT2A间的动态平衡,即健康肝组织中MAT1A高表达、MAT2A低表达[7],而在肝细胞癌中MAT1A转变成MAT2A,MAT1A表达降低、MAT2A增高[3, 8].所以,调控MAT1A/ MAT2A间的动态平衡可能成为肝细胞癌防治的关键.因此本文通过分析MAT1A和MAT2A与肝细胞癌的关系,进一步总结了MAT1A/MAT2A转化在肝细胞癌中的研究进展.

1 MAT1A与肝细胞癌

在哺乳动物中,MAT1A主要表达于大多数肝细胞,主要编码催化亚基MATα1.MATα1由396个氨基酸组成,包含MATⅠ和MATⅢ两种同工酶.单分子的MATα1常见于细胞核中,可以与致癌基因重组人p53和DNA损伤调节蛋白1(p53 and DNA damage regulated gene 1,PDRG1)结合,导致DNA甲基化水平降低.PDRG1在急性肝损伤和肝细胞癌中表达均增高,从而减少MATα1的表达[9-10].

1.1 MAT1A在肝细胞癌中低表达并抑制癌细胞增殖

MAT1A在人胚胎时期肝脏中表达含量极低,随着机体的生长发育,在正常肝脏中表达水平逐渐升高;而在有肝脏疾病的患者中其表达下降,尤其在肝细胞癌组织中则显著降低甚至停止表达[11-12].通过收集癌症基因图谱(the cancer genome atlas,TCGA)获取肝细胞癌样本分析,发现371例MAT1A的表达明显低于癌旁组织.提示MAT1A的不足可能是致肝细胞癌的关键,上调MAT1A有望抑制此种癌症的发生发展.

与MAT1A在肝细胞癌中的重要作用一致,敲除MAT1A基因的小鼠可自发形成肝细胞癌.而且在体外实验中,MAT1A高表达的癌细胞生长速度则明显减慢.正常肝细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)活性由双特异性磷酸酶1(dual-specificity phosphatase 1,DUSP1)控制,可通过磷酸化核内转录因子激活ERK途径从而参与细胞增殖过程.另外,持续激活ERK信号通路则可促进转化生长因子β(transforming growth factor-β,TGF-β)介导的癌细胞增殖[13-14].文献提示[14-16],沉默MAT1A可下调DUSP1,解除对ERK信号的控制从而促进肝细胞癌的进程,还可通过诱导肝激酶B1(liver kinase B1,LKB1)和AMP-活化蛋白激酶(AMP-activated protein kinase,AMPK)抑制癌细胞凋亡.其中AMPK活化可增加正常肝细胞人抗原R(human antigen R,HuR)的含量,促进细胞生长[17].MAT是细胞存活的关键,可以催化甲硫氨酸与三磷酸腺苷(adenosine triphosphate,ATP)结合形成SAMe,通过上调MAT1A则可抑制LKB1和AMPK的活性,促进癌细胞凋亡.

1.2 MAT1A与癌细胞侵袭转移

MAT1A在肝细胞癌的侵袭转移方面也发挥着重要作用[18].通过TCGA进一步分析发现,肝细胞癌中Ⅰ级、Ⅱ级和Ⅲ级中MAT1A的表达均较癌旁组织明显下降,而且随着分级程度的加深,MAT1A降低幅度更明显.另有报道提示[19],皮下接种Hep3B细胞的裸鼠移植瘤中3种microRNAs(miRNAs)——miR-664、miR-495-3p和miR-495的表达均明显上调,可促进移植瘤的形成与转移,而维持MAT1A的固有水平则可阻碍上述miRNAs介导的肿瘤发生.

1.3 MAT1A与肝细胞的预后

在单变量生存分析中,MAT1A的低表达与缩短患者生存期有显著的相关性.MAT1A的低表达可能与肿瘤进展有关,可能是肝细胞癌患者预后不良的一个独立因素[20].同时,有研究者[21]通过动物模型和人类肝细胞癌组织发现,MAT1A的表达降低与疾病恶化和更差的预后关联.并且通过TCGA基因数据库筛查,我们可以得到MAT1A基因与患者预后的关系,即MAT1A高表达的癌组织患者生存率远高于低表达的患者.

2 MAT2A与肝细胞癌

MAT2A大部分表达于肝外组织,此外在肝星状细胞(hepatic stellate cells,HSCs)和Kupffer细胞(Kupffer cell,KC)中也有表达,编码催化亚基MATα2[22].MATα2是由395个氨基酸构成的蛋白质,主要与MAT2B编码的β调节亚基共同组成MAT同工酶Ⅱ[11, 23].

2.1 MAT2A在肝细胞癌中表达升高,促进癌细胞增殖

正常情况下,在胎儿肝脏中主要表达MAT2A, 随着发育成熟逐渐会被MAT1A替代.当肝细胞癌发生时,MAT2A逐渐取代MAT1A,因此MAT1A/MAT2A的比值下降[24].TCGA数据库筛选获取的371例癌组织中,MAT2A表达明显高于正常组织,提示MAT2A在肝细胞癌中表达升高.下调MAT2A的表达,可能成为有效逆转肝细胞癌发生发展的新思路.

MAT2A与细胞增殖信号紧密联系,进而调控细胞周期进程[25].沉默HepG2细胞株中MAT2A的表达可减少细胞内SAMe并限制多胺生物合成.阻止瘦素(leptin)的促生存信号[26],这对细胞生长至关重要.另有报道称[27],MATα2的诱导可增强肝癌细胞聚胺生物合成,而增加聚胺类化合物也会通过促进激活蛋白1(activator protein 1,AP-1)转录上调MAT2A的表达.在癌细胞中,MATα2泛素化被证实是其翻译后的结果,一方面可作为转录因子诱导Bcl-2表达,另一方面则通过与Bcl-2结合,增加其稳定性[28-29].在肝细胞癌中,其他MAT2A转录后修饰如泛素化和乙酰化也十分重要.在癌组织中,MATα2与p300(E1A结合蛋白)结合,可介导赖氨酸残基81(K81)乙酰化,导致蛋白质泛素连接酶E3组件n-识别蛋白4 (E3 component N-recognin 4,UBR4)介导的泛素化显著下降[30].MATα2蛋白累积可促进肿瘤细胞增殖,尤其是癌症发展.与癌旁组织相比,肝细胞癌组织内MATα2 -K81复合物乙酰化作用降低还与组蛋白去乙酰化酶3(histone deacetylase,HDAC3)的表达增加有关[3].

2.2 MAT2A与癌细胞侵袭转移

缺氧诱导因子1α(hypoxia inducible factor,HIF-1α)在肿瘤组织中高表达,与癌细胞转移相关的基质金属蛋白酶2(matrixmetalloproteinase,MMP-2)呈正相关,预示肝癌细胞发展中HIF-1α在癌组织中的表达与癌细胞高度侵袭转移倾向有关[31].研究发现[32-33],在缺氧条件下HIF-1α也可以增强人MAT2A的启动子活性,参与MAT2A表达上调.这可能成为肝细胞癌发展过程中MAT2A表达上调的又一机制.同时,在TCGA基因谱图中也表示肝细胞癌的各个分级中,MAT2A表达明显高于癌旁组织,特别是肝细胞癌的Ⅲ级阶段,较Ⅰ级升高最明显.说明MAT2A的表达与肝细胞癌分级可能存在重要关联.

2.3 MAT2A与肝细胞癌的预后

研究者分析[34],210例肝细胞癌患者MAT2A的表达水平与年龄(≥60)、血清AFP>200 μg/L相关.癌组织中MAT2A表达过高可作为独立因素,预测到肝切除术后1年内复发率的升高.在没有微血管浸润的患者中,高表达MAT2A也是早期复发的独立预测因子.故肝细胞癌中MAT2A的过表达可能是预测和监测肿瘤复发的有用生物标志物,尤其在肝切除术后.TCGA数据库也显示,在肝细胞癌发展的各个级别中,高表达MAT2A的患者生存率均低于低表达的患者,尤其是高分级的肝细胞癌患者MAT2A表达高,生存率明显下降.

3 MAT1A/MAT2A转换在肝细胞癌中的关键作用

SAMe作为生物细胞的主要甲基供体,其合成及利用场所主要在肝脏中,可以调控肝细胞的发育和凋亡,一旦缺乏将会引起甲基化异常,出现肝细胞癌变[35-36].MAT作为机体内SAMe合成的唯一催化酶系,基因异常失活会直接影响到SAMe的表达水平,进而影响正常肝脏向肝细胞癌的发展进程.正常情况下,在胎儿肝脏中主要表达MAT2A,随着生长发育逐渐被MAT1A替代;反之,如果MAT1A逐渐被MAT2A代替,就可能造成肝细胞代谢异常,引发癌变.

在肝细胞癌发生过程中,下调MAT1A基因的同时显著上调MAT2A的表达,称为MAT1A/ MAT2A开关[22].有报道称[22],正常肝细胞中MAT1A/MAT2A处于动态平衡,影响着细胞内SAM稳态,一旦MAT1A/MAT2A这个开关被打开,即MAT1A向MAT2A转变,肝脏去分化,使SAMe生物合成减少,增强肝脏的增殖信号,进而导致肝细胞癌.同时发现在癌组织中,MAT1A/MAT2A开关与DNA低甲基化、DNA修复、基因组不稳定性及信号上调有关,包括c-MYC过表达、多胺合成、PI3K/AKT、NF-κB途径和LKB1/AMPK的上调[37-38].这表明MAT1A/ MAT2A水平在调控癌症发展中有重要作用.促进MAT2A向MAT1A转化、下调MAT2A、上调MAT1A,进而提高MAT1A/MAT2A的比值可能成为肝细胞癌治疗的关键.

DNA甲基化是表观遗传学的重要组成部分,原癌基因低甲基化和抑癌基因高甲基化均属于甲基化异常,通常DNA启动子异常甲基化发生在肝细胞癌的早期.有研究发现[39],MAT1A启动子在肝细胞癌组织中高甲基化而MAT2A则表现为低甲基化,提示MAT1A/MAT2A的启动子区域甲基化异常也可能与肝细胞癌发生早期有关.

DNA甲基化过程是在DNA甲基转移酶(DNA methyltransferases,DNMTs)作用下催化并维持的[40].研究发现[21],MAT1A启动子甲基化程度在肝细胞癌组织中远远高于相邻的非肿瘤组织,在癌组织中MAT1A启动子区域CpG甲基化,而在相应的癌旁组织中呈现低甲基化.在特异性DNA甲基转移酶抑制剂5-氮杂-2′-脱氧胞苷作用下,可明显促进MAT1A mRNA与蛋白质的表达,逆转MAT1A启动子的甲基化并诱导SAMe的表达,从而抑制Huh7细胞增殖[5].DNMTs主要包括DNMT1和DNMT3两种,其中DNMT1主要维持甲基化状态,而DNMT3分为DNMT3A和3B两种酶,是主要的从头甲基化酶[41].根据TCGA数据库分析结果,显示MAT1A与DNMT1、DNMT3A和DNMT3B两两间均存在负相关关系.并且进一步通过肝细胞癌数据库的基因表达谱(gene expression omnibus,GEO)分析,发现在GSE25097的肝细胞癌样本中,MAT1A明显下调,而DNMT1、DNMT3A和DNMT3B表达上调,并且MAT1A与DNMT1、DNMT3A和DNMT3B两两间均也存在负相关关系(表 1).

Table 1 Expression and correlation analysis of MAT1A/MAT2A and DNMT1/DNMT3A/DNMT3B 表 1 MAT1A/MAT2A和DNMT1/DNMT3A/DNMT3B的表达及相关性分析

MAT2A维持SAMe的稳态是基因组甲基化状态的重要标志.通过分析GSE25097的268例肝细胞癌样本,发现MAT2A表达明显上调的同时,MAT2A与DNMT1、DNMT3A和DNMT3B两两间呈正相关,这表明MAT2A的甲基化异常也可能和DNMTs表达有关(表 1).同时,有研究者发现缺氧诱导基因DNA去甲基化是通过激活肝癌细胞中HIF-1转录、上调MAT2A来实现的[31].在肝细胞癌的发展过程中,SAMe浓度下降,可导致DNA甲基化水平降低,将引起某些致癌因子C-myc、C-Ha-His和C-Ki-ras等的表达上调.因此,MAT2A甲基化程度在肝细胞癌组织中较正常组织明显降低,提示MAT2A促进肿瘤细胞生长还与其DNA甲基化有关.肝细胞癌进程中,通过下调MAT2A表达,可有效抑制癌细胞生长[42].在已确定的4个顺式作用元件和反式激活因子Sp1、c-Myb、NF-κB和AP-1中,肿瘤坏死因子α(tumour necrosis factor-α,TNF-α)可通过NF-κB和AP-1上调MAT2A.降低细胞内SAMe含量不仅会直接诱导MAT2A表达,还会影响细胞周期蛋白(cyclin)D1和D2的表达,解除对肝细胞生长因子(hepatocyte growth factor,HGF)丝裂酶原活化的抑制,进而激活HGF,上调MAT2A的表达[43-44].

综上,表达MAT1A的细胞,SAMe浓度和DNA甲基化水平较高,细胞生长减缓,而表达MAT2A的细胞,细胞内SAMe浓度和DNA甲基化水平均降低,细胞生长加速[19].因此,MAT1A/ MAT2A启动子区域甲基化异常影响MAT1A/2A动态平衡,进而作用于肝细胞癌的发生发展.王栋峰等[39]观察肝细胞癌中乙肝病毒X(hepatitis B virus X,HBx)蛋白对MAT1A和MAT2A基因启动子的甲基化状态的影响,分析了78例肝细胞癌患者组织,发现HBx能通过某些途径引起MAT1A启动子高甲基化、MAT2A启动子低甲基化来改变MATs的表达状态.图 1总结了MAT1A/MAT2A对肝细胞癌各信号通路的影响.

Fig. 1 Effects of MA1A/MAT2A on signal pathways of hepatocellular carcinoma(HCC) 图 1 MAT1A/MAT2A对肝细胞癌的影响
4 总结与展望

总之,肝细胞癌是一个多因素、多途径参与的复杂病理过程.在肝细胞癌发展早期,因为缺乏灵敏、有用的筛查指标,通常不能及时发现;当患者出现典型症状或检测血清指标异常时,已经进入侵袭、转移等肝细胞癌晚期,这是预后差的原因之一.目前,手术治疗仍是治疗肝细胞癌的首选手段,但术后复发和转移率很高,而临床上又缺乏有效的预后检测指标,又是导致患者预后差的另一原因.所以寻找有效的预后检测指标对研究肝细胞癌的发病机制和预后具有重要意义.MAT基因无论是在肝细胞癌发展初期,还是侵袭迁移的发展晚期,皆有明显的表达水平变化,故MAT基因或可作为用于肝细胞癌预后复发预测的生物标志物[45-47].

MAT1A/MAT2A的表达水平贯穿了整个肝脏疾病的发展过程[48-49].在肝损伤和肝细胞癌中,癌组织MAT1A表达减少,其编码的酶MATⅠ/Ⅲ失活,MAT2A则表达增强[3],SAMe水平降低,MAT1A向MAT2A转化,与CpG高甲基化和MAT1A启动子的组蛋白H4脱乙酰化作用有关[35],而在MAT2A启动子区域则呈现CpG低甲基化和组蛋白H4乙酰化,受肿瘤发生的表观遗传影响.提示MAT1A/MAT2A平衡调控对肝细胞癌的防治将具有非常重要的作用,可能为探究肝细胞癌防治靶点寻找一条新的思路.

参考文献
[1]
Zucmanrossi J, Nault J C, Zender L. Primary liver carcinomas can originate from different cell types: a new level of complexity in hepatocarcinogenesis. Gastroenterology, 2013, 145(1): 53-55. DOI:10.1053/j.gastro.2013.05.024
[2]
Lu S C, Mato J M. S-adenosylmethionine in liver health, injury, and cancer. Physiological Reviews, 2012, 92(4): 1515-1542. DOI:10.1152/physrev.00047.2011
[3]
Ramani K, Lu S C. Methionine adenosyltransferases in liver health and diseases. Liver Research, 2017, 1(2): 103-111. DOI:10.1016/j.livres.2017.07.002
[4]
Anstee Q M, Day C P. S-adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility. Journal of Hepatology, 2012, 57(5): 1097-1109. DOI:10.1016/j.jhep.2012.04.041
[5]
Markham G D, Pajares M A. Structure-function relationships in methionine adenosyltransferases. Cellular & Molecular Life Sciences, 2009, 66(4): 636-648.
[6]
汪群, 陆卫军, 汪洋, 等. MAT2B基因在肝癌组织的表达及其临床意义. 中华实验外科杂志, 2017, 34(4): 656-658.
Wang Q, Lu W J, Wang Y, et al. Chinese Journal of Experimental Surgery, 2017, 34(4): 656-658. DOI:10.3760/cma.j.issn.1001-9030.2017.04.038
[7]
Nordgren K K, Peng Y, Pelleymounter L L, et al. Methionine adenosyltransferase 2A/2B and methylation: gene sequence variation and functional genomics. Drug Metabolism & Disposition the Biological Fate of Chemicals, 2011, 39(11): 2135-2147.
[8]
Ramani K, Yang H, Kuhlenkamp J, et al. Changes in the expression of methionine adenosyltransferase genes and S-adenosylmethionine homeostasis during hepatic stellate cell activation. Hepatology, 2010, 51(3): 986-995.
[9]
Reytor E, Pérezmiguelsanz J, Alvarez L, et al. Conformational signals in the C-terminal domain of methionine adenosyltransferase Ⅰ/Ⅲ determine its nucleocytoplasmic distribution. Faseb Journal Official Publication of the Federation of American Societies for Experimental Biology, 2009, 23(10): 3347-3360. DOI:10.1096/fj.09-130187
[10]
Pérez C, Pérezzúñiga F J, Garrido F, et al. The oncogene PDRG1 is an interaction target of methionine adenosyltransferases. Plos One, 2016, 11(8): e0161672. DOI:10.1371/journal.pone.0161672
[11]
Igarashi K, Katoh Y. Metabolic aspects of epigenome: coupling of S-adenosylmethionine synthesis and gene regulation on chromatin by SAMIT module. Springer Netherlands, 2013, 61(61): 105-118.
[12]
Liu W J, Ren J G, Li T, et al. 5-Aza-2 < -deoxycytidine induces hepatoma cell apoptosis via enhancing methionine adenosyltransferase 1A expression and inducing S-adenosylmethionine production. Asian Pacific Journal of Cancer Prevention Apjcp, 2013, 14(11): 6433-6438. DOI:10.7314/APJCP.2013.14.11.6433
[13]
Kato H, Naiki-Ito A, Naiki T, et al. Connexin 32 dysfunction promotes ethanol-related hepatocarcinogenesis via activation of Dusp1-Erk axis. Oncotarget, 2016, 7(2): 2009-2021.
[14]
Nguyen L N, Furuya M H, Wolfraim L A, et al. Transforming growth factor-beta differentially regulates oval cell and hepatocyte proliferation. Hepatology, 2007, 45(1): 31-41. DOI:10.1002/(ISSN)1527-3350
[15]
Lei L, Zhao G, Zhe S, et al. The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncology Letters, 2016, 12(5): 3045-3050. DOI:10.3892/ol.2016.5110
[16]
Tomasi M L, Ramani K, Lopitz-Otsoa F, et al. S-Adenosylmethionine regulates dual-specificity mitogen-activated protein kinase phosphatase expression in mouse and human hepatocytes. Hepatology, 2010, 51(6): 2152-2161. DOI:10.1002/hep.23530
[17]
Li N, Huang D, Lu N, et al. Role of the LKB1/AMPK pathway in tumor invasion and metastasis of cancer cells. Oncology Reports, 2015, 34(6): 2821-2826. DOI:10.3892/or.2015.4288
[18]
Maldonado L Y, Arsene D, Mato J M, et al. Methionine adenosyltransferases in cancers: mechanisms of dysregulation and implications for therapy. Experimental Biology & Medicine, 2018, 243(2): 107-117.
[19]
Yang H, Cho M E, Li T W, et al. MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma. Journal of Clinical Investigation, 2013, 123(1): 285-298. DOI:10.1172/JCI63861
[20]
Jin Z, Chen G, Bing Y, et al. Hypermethylation-repressed methionine adenosyltransferase 1A as a potential biomarker for hepatocellular carcinoma. Hepatology Research, 2013, 43(4): 374-383. DOI:10.1111/hepr.2013.43.issue-4
[21]
Frau M, Tomasi M L, Simile M M, et al. Role of transcriptional and posttranscriptional regulation of methionine adenosyltransferases in liver cancer progression. Hepatology, 2012, 56(1): 165-175. DOI:10.1002/hep.25643
[22]
Ramani K, Donoyan S, Tomasi M L, et al. Role of methionine adenosyltransferase α2 and β phosphorylation and stabilization in human hepatic stellate cell trans-differentiation. Journal of Cellular Physiology, 2015, 230(5): 1075-1085. DOI:10.1002/jcp.24839
[23]
Halim A B, Legros L, Chamberlin M E, et al. Regulation of the human MAT2A gene encoding the catalytic alpha 2 subunit of methionine adenosyltransferase, MAT Ⅱ: gene organization, promoter characterization, and identification of a site in the proximal promoter that is essential for its activity. Journal of Biological Chemistry, 2001, 276(13): 9784-9791. DOI:10.1074/jbc.M002347200
[24]
Garcíatrevijano E R, Latasa M U, Carretero M V, et al. S-adenosylmethionine regulates MAT1A and MAT2A gene expression in cultured rat hepatocytes: a new role for S-adenosylmethionine in the maintenance of the differentiated status of the liver. Faseb Journal, 2000, 14(15): 2511-2518. DOI:10.1096/fj.00-0121com
[25]
Zhao C, Wu H, Qimuge N, et al. MAT2A promotes porcine adipogenesis by mediating H3K27me3 at Wnt10b locus and repressing Wnt/Î2-catenin signaling. Biochim Biophys Acta, 2018, 1863(2): 132-142. DOI:10.1016/j.bbalip.2017.11.001
[26]
Ramani K, Yang H, Xia M, et al. Leptin's mitogenic effect in human liver cancer cells requires induction of both methionine adenosyltransferase 2A and 2β. Hepatology, 2008, 47(2): 521-531.
[27]
Tomasi M L, Ryoo M, Skay A, et al. Polyamine and methionine adenosyltransferase 2A crosstalk in human colon and liver cancer. Experimental Cell Research, 2013, 319(12): 1902-1911. DOI:10.1016/j.yexcr.2013.04.005
[28]
Lauda T M, Minjung R, Komal R, et al. Methionine adenosyltransferase α2 sumoylation positively regulate Bcl-2 expression in human colon and liver cancer cells. Oncotarget, 2015, 6(35): 37706-37723.
[29]
Zhang Q, Ma S, Liu B, et al. Chrysin induces cell apoptosis via activation of the p53/Bcl-2/caspase-9 pathway in hepatocellular carcinoma cells. Experimental & Therapeutic Medicine, 2016, 12(1): 469-474.
[30]
Yang H B, Xu Y Y, Zhao X N, et al. Acetylation of MAT Ⅱα represses tumour cell growth and is decreased in human hepatocellular cancer. Nature Communications, 2015, 6(1): 1-12.
[31]
Wang B, Ding Y, Fan P, et al. Expression and significance of MMP2 and HIF-1α in hepatocellular carcinoma. Oncology Letters, 2014, 8(2): 539-546. DOI:10.3892/ol.2014.2189
[32]
Liu Q, Liu L, Zhao Y, et al. Hypoxia induces genomic DNA demethylation through the activation of HIF-1α and transcriptional upregulation of MAT2A in hepatoma cells. Molecular Cancer Therapeutics, 2011, 10(6): 1113-1123. DOI:10.1158/1535-7163.MCT-10-1010
[33]
Ramin S, Azar F P, Malihe H. Methylene blue as the safest blue dye for sentinel node mapping: emphasis on anaphylaxis reaction. Acta Oncologica, 2011, 50(5): 729-731. DOI:10.3109/0284186X.2011.562918
[34]
An J, Na S K, Shim J H, et al. Histological expression of methionine adenosyl transferase (MAT) 2A as a post-surgical prognostic surrogate in patients with hepatocellular carcinoma. J Surg Oncol, 2018, 117(5): 892-901. DOI:10.1002/jso.v117.5
[35]
Murín R, Vidomanová E, Kowtharapu B S, et al. Role of S-adenosylmethionine cycle in carcinogenesi. Gen Physiol Biophys, 2017, 36(5): 513-520. DOI:10.4149/gpb_2017031
[36]
Xiao Y, Su X, Huang W, et al. Role of S-adenosylhomocysteine in cardiovascular disease and its potential epigenetic mechanism. International Journal of Biochemistry & Cell Biology, 2015, 67(10): 158-166.
[37]
Wen Z, Sviripa V, Xi C, et al. Fluorinated N, N-dialkylaminostilbenes repress colon cancer by targeting methionine S-adenosyltransferase 2A. Acs Chemical Biology, 2013, 8(4): 796-803. DOI:10.1021/cb3005353
[38]
Albers E. Metabolic characteristics and importance of the universal methionine salvage pathway recycling methionine from 5'-methylthioadenosine. Iubmb Life, 2009, 61(12): 1132-1142. DOI:10.1002/iub.v61:12
[39]
王栋锋, 刘志苏, 刘权焰, 等. 肝细胞癌中HBX和MATs基因启动子甲基化的关系. 中华实验外科杂志, 2011, 28(2): 242-244.
Wang D F, Liu Z S, Liu Q Y, et al. Chinese Journal of Experimental Surgery, 2011, 28(2): 242-244. DOI:10.3760/cma.j.issn.1001-9030.2011.02.028
[40]
Hong F, Zhao Z, Cheng Y, et al. Genome-wide profiling of DNA methylation reveals preferred sequences of DNMTs in hepatocellular carcinoma cells. Tumor Biology, 2016, 37(1): 877-885. DOI:10.1007/s13277-015-3202-z
[41]
Pellerito C, Morana O, Ferrante F, et al. Synthesis, chemical characterization, computational studies and biological activity of new DNA methyltransferases (DNMTs) specific inhibitor. Epigenetic regulation as a new and potential approach to cancer therapy. Journal of Inorganic Biochemistry, 2015, 150(9): 18-27.
[42]
Zhang W, Sviripa V, Watt D, et al. Abstract 5388: Methionine S-adenosyltransferase 2A (MAT2A) inhibitors for cancer treatment. Cancer Research, 2015, 75(15): 18-22.
[43]
Carmel J, Arish A, Shoshany G, et al. Heparanase accelerates the proliferation of both hepatocytes and endothelial cells early after partial hepatectomy. Experimental & Molecular Pathology, 2012, 92(2): 202-209.
[44]
Zhang T, Zheng Z, Liu Y, et al. Overexpression of methionine adenosyltransferase Ⅱ alpha (MAT2A) in gastric cancer and induction of cell cycle arrest and apoptosis in SGC-7901 cells by shRNA-mediated silencing of MAT2A gene. Acta Histochemica, 2013, 115(1): 48-55. DOI:10.1016/j.acthis.2012.03.006
[45]
Liu Q, Chen J, Liu L, et al. The X protein of hepatitis B virus inhibits apoptosis in hepatoma cells through enhancing the methionine adenosyltransferase 2A gene expression and reducing S-adenosylmethionine production. Journal of Biological Chemistry, 2011, 286(19): 17168-17180. DOI:10.1074/jbc.M110.167783
[46]
Jung Y S. Metabolism of sulfur-containing amino acids in the liver: a link between hepatic injury and recovery. Biological & Pharmaceutical Bulletin, 2015, 38(7): 971-974.
[47]
Wu C, Liu Q. MAT gene and liver cancer. Medical Journal of Wuhan University, 2008, 29(4): 559-562.
[48]
Pajares M A, Alvarez L, Pérez-Sala D. How are mammalian methionine adenosyltransferases regulated in the liver? A focus on redox stress. Febs Letters, 2013, 587(12): 1711-1716. DOI:10.1016/j.febslet.2013.04.034
[49]
Anstee Q M, Day C P. S-adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility. J Hepatol, 2012, 57(5): 1097-1109. DOI:10.1016/j.jhep.2012.04.041
中国科学院生物物理研究所和中国生物物理学会共同主办
0

文章信息

李子涵, 熊婷, 熊晓丽, 卢子贤, 周志刚, 涂剑
LI Zi-Han, XIONG Ting, XIONG Xiao-Li, LU Zi-Xian, ZHOU Zhi-Gang, TU Jian
甲硫氨酸腺苷转移酶1A/2A平衡与肝细胞癌
Equilibrium of Methionine Adenosine Transferase 1A / 2A and Hepatocellular Carcinoma
生物化学与生物物理进展, 2018, 45(12): 1232-1239
Progress in Biochemistry and Biophysics, 2018, 45(12): 1232-1239
http://dx.doi.org/10.16476/j.pibb.2018.0139

文章历史

收稿日期: 2018-05-05
接受日期: 2018-06-21

相关文章

工作空间