修回日期: 2011-11-12
接受日期: 2012-02-17
在线出版日期: 2012-02-18
γ-氨基丁酸(γ-Aminobutyric acid, GABA)是成年哺乳动物脑内的主要抑制性神经递质, 他在中枢神经、外周神经和外周非神经组织中表达. 根据GABA受体对激动剂及拮抗剂敏感性的不同, 目前分为A、B、C三型. 近来发现, GABA对肿瘤发生发展具有调控作用. 因GABA受体及受体亚单位表达多样化、受体介导的胞内信号传导通路的差异, 其对肿瘤细胞的调控作用及相关机制不同. 研究发现GABA与其受体结合可激活或抑制cAMP信号通路、MAPKs家族的ERK1/2信号通路, 从而调控多种肿瘤细胞的增殖和转移. 随着研究进一步深入, GABA在肿瘤诊断、预后判断和生物治疗等方面的潜在价值将逐步显现, 本文就此领域的最新进展予以综述.
引文著录: 施言, 王少慧, 张发明. γ-氨基丁酸及其受体在肿瘤发生发展中的作用. 世界华人消化杂志 2012; 20(5): 399-404
Revised: November 12, 2011
Accepted: February 17, 2012
Published online: February 18, 2012
Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the adult mammalian brain and it is also expressed in the central nervous system, peripheral nerves and peripheral non-neural tissues. Recent studies have shown that GABA is involved in the proliferation and migration of tumor cells and other processes of tumor development. According to different sensitivity to agonists and antagonists, GABA receptors have been classified into three types: A, B and C. GABA receptors and their receptor subunits are involved in complicated regulation of tumor cells. Many studies have demonstrated that GABA binding to its receptors can activate or inhibit the cAMP signaling pathway and the MAPK/ERK pathway, and regulate cancer cell proliferation and migration. The potential value of GABA in cancer diagnosis, prognostic prediction and biotherapy has been gradually revealed. In the present article, we reviewed the recent progress in understanding the role of GABA and its receptors in carcinogenesis.
- Citation: Shi Y, Wang SH, Zhang FM. Role of γ-aminobutyric acid and its receptors in carcinogenesis. Shijie Huaren Xiaohua Zazhi 2012; 20(5): 399-404
- URL: https://www.wjgnet.com/1009-3079/full/v20/i5/399.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i5.399
γ-氨基丁酸(γ-Aminobutyric acid, GABA)是成年哺乳动物脑内的主要抑制性神经递质, 他在中枢神经、外周神经和外周非神经组织中表达[1,2]. GABA通过离子通道型受体-GABA A受体、C受体，以及促代谢型受体-GABA B受体发挥作用. 目前已经发现GABA受体在外周组织中表达[2-4], 这提示GABA在外周组织中的存在可能不仅局限于充当神经递质. 最早在1990年,有研究将亚硝基胍诱导的大鼠胃癌与GABA B受体联系起来[5]. 之后的许多研究揭示了GABA及其各种受体在肿瘤发生中的作用和机制[6-14]. GABA与其受体结合可激活或抑制cAMP信号通路、MAPKs家族的ERK1/2信号通路, 从而调控多种肿瘤细胞的增殖和转移. 最近发现, GABA各种受体以及受体亚单位表达多样化也是介导GABA效应的机制之一, GABA A受体α1亚单位能够与动力相关蛋白TRAK1结合[15], 我们的研究进一步发现TRAK1是一种重要的肿瘤标志物,尤其是可能与肿瘤细胞受神经体液调节及分泌细胞内黏液有关[16]. 本文就GABA及其各种受体在多种肿瘤中表达分布及其在肿瘤细胞增殖、转移等发展过程中的机制予以综述.
GABA是一个非蛋白组分的氨基酸, 在细菌、植物和动物中广泛存在. 1950年, GABA被首次发现存在于哺乳动物脑中[17,18]. 后来的研究进一步发现, 谷氨酸脱羧酶(glutamate decarboxylase, GAD)为催化谷氨酸向GABA转化的关键酶[19]. 除此之外, GABA还可以通过多胺途径[20]、鸟氨酸途径[21-23]和高肌肽[24]途径生成, 这些途径可能在某些特定的条件下发挥重要功能. 20世纪50年代末至60年代初, Curtis等[25]发现GABA对脊髓神经元有抑制作用. 据此, Krnjevic等[26]在1963年提出, 谷氨酸和GABA等氨基酸类可能是中枢神经递质. 不过, 相对于当时大家所熟知的外周神经递质乙酰胆碱神经兴奋作用, 这个发现一直被冷落了数年. 到20世纪70年代初期, 借助特异性的GABA受体抑制剂荷包牡丹碱(bicuculline), 人们才认识到GABA为抑制性中枢神经递质.
根据GABA受体对激动剂及拮抗剂敏感性的不同, 目前将GABA受体分为A、B、C三型(表1).
| 受体类型 | 性质 | 亚单位组成 | 激动剂或拮抗剂 | 分布区域 |
| A受体 | 氯离子通道 | 五聚体, 7个亚类: α1-6, β1-3, γ1-3, δ, ε, θ和π | 拮抗剂: 荷包牡丹碱 | 胃G细胞、视神经、三叉神经、肠道神经、肾上腺、小肠、肝脏、肾脏、胰腺、垂体、肺 |
| B受体 | G蛋白藕联受体 | 二聚体 R1, R2 | 激动剂: 巴氯芬 | 胃、肾上腺、垂体、脾脏、肾脏、小肠 |
| C受体 | 五聚体 ρ1、ρ2、ρ3 | 视网膜、丘脑、海马、垂体、脊髓、小脑、肺、胸腺、胃肠道 |
GABA A受体是氯离子通道, 其特异性拮抗剂为荷包牡丹碱. GABA A受体是由5个亚单位组成的五聚体, 其受体亚单位根据氨基酸序列的同源性分为7个亚类: α1-6, β1-3, γ1-3, δ, ε, θ和π. GABA A受体的分布不只局限于中枢神经系统, 还包括胃G细胞[27]、视神经[28]、三叉神经[29]、肠道神经[30,31]、肾上腺[4,32]、小肠[4,33]、肝脏[34]、肾脏[35]、胰腺[27]、垂体[36]和肺[37].
GABA B受体为G蛋白藕联受体, 对荷包牡丹碱不敏感, 但能被特异性激动剂巴氯芬(baclofen)所激活. GABA B受体是由2个不同基因编码的亚单位(R1, R2)组成的二聚体. GABA B受体除在中枢神经系统表达外, 在许多的外周组织如胃[38]、肾上腺[38]、垂体[38]、脾脏[39]、肾脏[38,39]和小肠[40,41]也参与表达.
把对荷包牡丹碱及巴氯芬都不敏感的GABA受体称为GABA C受体. GABA C受体也是由5个亚单位组成的五聚体. 目前已知的亚单位有ρ1、ρ2、ρ3. GABA C受体最早被发现存在于视网膜中[42], 此外, 在小脑[43]、肺[44]、丘脑[45]、海马[45]、垂体[45]、脊髓[45]、胸腺[46]和胃肠道中也有表达[45,47].
GABA通过不同受体途径对肿瘤细胞增殖和转移能力的影响有其特异性. 不同部位、不同的细胞系, 由于其胞膜GABA受体亚单位组成及胞内信号传导通路的差异, 其调节作用及相关机制有所不同(表2).
| 受体类型 | 亚单位 | 信号通路 | 功能 |
| A受体 | |||
| π | MAPKs信号通路↑ | 促进胰腺癌细胞株KLM-1增殖[10] | |
| - | MAPKs家族的ERKl/2信号通路↑ | 抑制胆管癌细胞株Mz-ChA-1增殖和转移[8] | |
| - | MAPKs家族中的ERKl/2信号通路↑ | 促进胃癌细胞株KATO III增殖[54] | |
| α3 | 促进肝癌细胞株HepG2增殖[11] | ||
| β3 | 抑制肝癌细胞株PLC/PRF/5增殖[53] | ||
| B受体 | |||
| - | cAMP信号通路↓ | 抑制去甲肾上腺素诱导的结肠癌细胞株SW480转移[57] | |
| - | cAMP信号通路↓ | 抑制肝癌细胞株Huh-7转移[58] | |
| - | cAMP信号通路↓ | 抑制肺癌细胞株NCL-H322增殖和转移[44] | |
| - | MAPKs家族的ERKl/2信号通路↑ | 抑制胆管癌细胞株Mz-ChA-1增殖和转移[8] | |
| - | MAPKs家族的ERKl/2、JNK和P38信号通路↑ | 促进肾细胞癌Caki-2株转移[9] | |
| - | 抑制大鼠胃癌生长[5] | ||
| - | 促进前列腺癌细胞株C4-2转移[6] | ||
| R2 | 促进甲状腺癌生长[48] | ||
| C受体 | |||
| - | MAPKs家族的ERKl/2信号通路↑ | 抑制胆管癌细胞株Mz-ChA-1增殖和转移[8] |
与正常细胞相比, 恶性肿瘤细胞中GABA A受体亚单位的表达有所不同. 甲状腺癌中表达GABA A受体α2亚单位, 不表达β2亚单位, 而正常甲状腺组织正好相反[48]. 利用消减杂交的技术发现, 神经母细胞瘤中高表达GABA A受体α2亚单位[49]. 通过计算机模拟查找肝癌、正常肝细胞差异表达基因与实验确认的方法, Li等[11]发现肝癌细胞过度表达α3亚单位. GABA A受体亚单位表达模式的差异除了与恶性肿瘤的快速增殖相关之外, 还可以作为判断预后的指标[49]. Liu等[13]发现GABA A受体α3亚单位在肺癌组织中表达增加, 且与肿瘤低分化相关.
新近研究显示, GABA A受体α1亚单位能够与动力相关蛋白TRAK1相互结合[15], Zhang等[16]进一步发现TRAK1不仅在兴奋组织中表达, 还在非兴奋组织和细胞中表达, 首次鉴定其为一种重要的肿瘤标志物, 其免疫组化检测对印戒细胞癌和黏液腺癌诊断的敏感性高达100%, 并据此推测TRAK1蛋白可能与肿瘤细胞受神经体液调节及分泌细胞内黏液有关. 该结果进一步被TRAK1在结肠癌组织中的诊断价值证实[50].Thorsen等[51]研究发现DLD1和Ls174T结直肠癌细胞系中, TRAK1基因是肿瘤特异性可变转录启动区的调控因子, Wnt信号通路可调控此基因表达. Brickley等[52]发现TRAK蛋白家族还可调控海马神经元轴突细胞线粒体运动功能. 以上研究提示, TRAK1蛋白作为GABA受体介导的效应分子, 在肿瘤调控的机制研究中, 已经受到科学家的关注.
Sun等[53]发现PLC/PRF/5肝癌细胞株表达GABA A受体β3亚单位, 但Chang、HepG2和HuH-7肝癌细胞株均不表达, 激活该受体亚单位可抑制此肿瘤细胞增殖. 而Liu等[11]发现体内或体外肝癌细胞株HepG2均过度表达GABA A受体α3亚单位, 降低其表达能够抑制肿瘤细胞增殖, 且效应呈剂量依赖性, 敲低此受体亚单位表达的HepG2细胞株无增殖效应. 另一项研究发现胰腺癌细胞株KLM-1过量表达GABA A受体π亚单位, GABA激动该受体后通过提高胞内钙离子浓度激活MAPKs信号通路促进肿瘤细胞增殖[10], 对B受体的抑制剂CGP35348的作用不敏感. 胃癌细胞株KATO Ⅲ表达GAD和GABA A受体, 不表达B受体, GABA激动A受体能够促进该肿瘤细胞增殖, 此增殖效应在10 μmol/L或1 μmol/L GABA浓度下最大, 主要激活MAPKs家族中的ERK1/2信号通路, 同时细胞周期素D1的表达增加[54].
在GABA对不同肿瘤细胞转移影响的研究中, GABA B受体, 即促代谢型受体, 引起了特别的关注. GABA B受体属于含有G蛋白藕联受体家族的成员, 与趋化因子受体和儿茶酚胺受体相关, 而后两种受体均参与调控白细胞和肿瘤细胞的转移[55,56]. 已有的研究表明GABA B受体参与了肺癌[44]、结肠癌[57]、前列腺癌[6]、肾癌细胞[9]的转移, 如GABA通过B受体能够促进前列腺癌细胞株C4-2迁移[6].
Maemura等[44]发现GABA能够通过B受体发挥抑制肺癌细胞株NCI-H322增殖和转移的作用, 其机制为抑制β-肾上腺素受体调控的环磷酸腺苷(cyclic AMP, cAMP)信号通路. Watanabe等[9]在人肾细胞癌Caki-2中研究了GABA对MAPKs信号通路活化的调控作用, 结果发现: GABA激活B受体促进MAPKs家族成员的磷酸化, 包括细胞外信号调节激酶1/2(extracellular signal-regulated kinase 1/2, ERKl/2)、c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)和P38. Lodewyks等[58]发现激活GABA B受体抑制cAMP信号通路可减少肝癌细胞株Huh-7转移, 但不影响肿瘤细胞增殖. Entschladen等[57]发现GABA激活B受体后可降低肿瘤细胞内cAMP浓度, 抑制由去甲肾上腺素诱导的结肠癌细胞株SW480的转移.
一系列的动物实验提示激动GABA B受体能够抑制体内肿瘤细胞增殖. Tatsuta等[7]用氧化偶氮甲烷诱导Wistar大鼠发生结肠癌, 以蝇蕈醇、巴氯芬干预, 结果巴氯芬可有效抑制肿瘤生长, 蝇蕈醇则无此作用, 这在Wistar大鼠胃癌模型中也得到了证实[59]. 国内一项实验结果表明, 巴氯芬在体内和体外试验中均可通过激活GABA B受体有效抑制肝癌细胞的生长[60]. 同时Biju等[61]观察到, 用硝基二乙胺诱导大鼠发生肝癌后, 肿瘤细胞GABA B受体表达增加.
GABA C受体涉及的信号通路研究较少. 有研究将胆管癌细胞系Mz-ChA-1注入裸鼠体内,发现GABA通过激动A受体、B受体和C受体, 磷酸化MAPKs家族的ERKl/2信号通路分子从而抑制肿瘤细胞的增殖和转移, 导致肿瘤凋亡增加, 体积缩小[8]. 由于肿瘤细胞与神经元细胞的生理结构和功能存在差异, 因而肿瘤细胞中的GABA受体途径应该有别于神经元细胞. GABA对肿瘤细胞的增殖及侵袭转移能力究竟是促进还是抑制? 又通过何种受体途径实现其调控作用? 在调控过程中, 还涉及哪些相关信号传导途径? 这些问题有待于更深入的研究.
目前关于GABA与肿瘤发生、发展之间关系的探讨工作还处于起步阶段. 本文综述了近几十年的文献, 着重总结了GABA及其各种受体在肿瘤增殖、转移方面的作用, 当然还可能存在着其他尚未被发现的受体类型及相关信号通路. 随着研究的深入, GABA及其受体在肿瘤治疗和预后判断等方面的潜在价值将逐步显现, 有可能成为肿瘤诊断与治疗的理想靶点.
γ-氨基丁酸是成年哺乳动物脑内的主要抑制性神经递质,目前发现GABA受体可在外周组织中表达,且与肿瘤发生发展相关. GABA与其相应受体结合可介导不同信号传导通路调控多种肿瘤细胞的增殖和转移, 从而成为近来肿瘤诊断和治疗的研究热点.
黄培林, 教授, 东南大学肿瘤学
目前大部分研究主要集中于cAMP信号传导通路和MAPKs家族信号传导通路. GABA对肿瘤细胞的增殖及侵袭能力究竟是促进还是抑制? 相应的具体机制又是什么? 这些仍是未来的研究方向.
本文初步探讨了GABA及其各种受体在肿瘤增殖、转移方面的作用. 随着研究进一步深入, GABA在肿瘤诊断、预后判断和生物治疗等方面的潜在价值将逐步显现, 本文就此领域的最新进展予以综述.
该文稿比较详尽综述了近20年来有关GABA及其受体在肿瘤发生发展过程作用的研究现况, 作者阅读了大量文献, 对于广大肿瘤研究者有一定的参考意义, 让更多的人关注和了解神经性递质在肿瘤中的作用.
编辑:曹丽鸥 电编:闫晋利
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