修回日期: 2004-08-09
接受日期: 2004-08-21
在线出版日期: 2004-10-15
近年研究发现HBV基因组中的X基因及其产物X蛋白(HBx)能够对肝细胞的凋亡起双向调控作用, 在HBV感染相关疾病的发生发展中起重要作用. 一方面, HBx可通过调节Caspases家族成员活性, 抑制p53的促凋亡活性, 激活Rel家族成员, 上调Survivin的表达等途径抑制肝细胞凋亡, 导致HCC发生.另一方面, HBx可通过拮抗c-FLIP的抑凋亡作用, 抑制p53的抗凋亡活性, 调节Bcl-2家族蛋白的表达, 上调c-myc及TGF-β1等的表达, 直接或间接作用于Fas-FasL, TNF或线粒体死亡途径, 增强死亡信号而促进细胞凋亡. 总之, HBx可能是通过多途径, 多环节和多因子参与的复杂机制对肝细胞的凋亡进行调节.
引文著录: 张生君, 王小众. HBx对肝细胞凋亡的双向调控及机制. 世界华人消化杂志 2004; 12(10): 2424-2428
Revised: August 9, 2004
Accepted: August 21, 2004
Published online: October 15, 2004
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12(10): 2424-2428
- URL: https://www.wjgnet.com/1009-3079/full/v12/i10/2424.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v12.i10.2424
近年来随着对HBV基因结构与功能的深入研究, 发现HBV基因组中的X基因及其产物X蛋白(HBx)能够对肝细胞的凋亡起调控作用, 在HBV感染所致的肝癌的发生发展中起重要作用[1]. 一方面, HBx能抑制肝细胞凋亡, 从而促进HCC的发生发展; 另一方面, 近年来多项研究表明HBx还具有诱导或促进肝细胞凋亡的作用, 该作用在HBV相关疾病中的具体作用还不甚清楚, 其中的具体机制也尚未阐明. 现对HBx对肝细胞凋亡的双向调控及其机制作一综述.
HBx是一种多功能蛋白, 能与多种蛋白相互作用, 表现出复杂多样的生物学活性. 在对肝细胞凋亡的调控方面, HBx表现出双向作用.HBx抑制肝细胞凋亡使具有潜在转化能力的突变获得积累, 细胞过度增生, 从而导致HCC发生. 然而, 近年来多项研究表明HBx能诱导[2-5]和促进凋亡[6-9], 且HBx表达量与凋亡率有量效关系[10]. HBx促进肝细胞凋亡在HBV感染相关疾病的发病机制中的具体作用还不甚清楚. 目前认为该作用可能促进肝炎的发展, 并在逃避宿主免疫反应时促进病毒向临近细胞播散. 据推测, HBV x基因可能通过促进肝细胞凋亡而诱导肝细胞再生和基因突变的积累, 最后导致细胞转化和HCC的发生[7]. 还有人认为, HBx对肝细胞凋亡的双向调控作用可能与HBV感染发展至HCC的长期性有关[2]. HBx引起肝细胞凋亡有可能存在着细胞的特异性和阶段性. 即对于不同的肝细胞以及HBV感染的不同阶段, HBV x基因可能在肝细胞凋亡方面发挥着不同的作用. 在早期阶段, HBx可能抑制凋亡, 促进HBV的增生. 在后期, HBx促进凋亡, 这种促凋亡效应可加速HBV的复制与播散. Koike et al[11]则认为HBx不管抑制还是促进细胞凋亡均可能导致肝细胞恶性转化, 从而有利于癌前期肝细胞的选择和克隆性增生.
Fas-FasL死亡受体途径和TNF死亡受体途径是诱导细胞凋亡的主要信号转导途径. Diao et al[12]将HBx(来自HBV慢性携带者)转染入人原代肝细胞、Chang 肝细胞及大鼠胚胎成纤维细胞, 发现HBx能使这些细胞免受Fas介导的凋亡, 对血清缺乏产生耐受性, 并且对TNF介导的凋亡也有一定抵抗保护作用. 其可能机制包括抑制caspase8和caspase3的活性, 抑制细胞色素C的释放, 上调SAPK/JNK活性而通过SEK1依赖的SAPKs/JNKs途径抑制细胞凋亡.
Caspases是一个日益增大的半胱氨酸蛋白酶家族, 是细胞凋亡的必要因子, 通常以酶原的形式存在, 包括死亡受体信号转导等在内的多种凋亡刺激均可引起caspases的活化, 形成信号转导级联反应, 最终导致细胞凋亡. 参与诱导凋亡的caspases分成两大类, 即启动酶和效应酶, 分别在死亡信号转导的上游和下游发挥作用. 经FADD(Fas-associated death domain protein)激活的caspase8属于启动酶, 在Fas和TNFR1诱导的细胞凋亡信号途径中皆发挥重要的作用. 其他的启动酶还有参与线粒体介导凋亡的caspase9及与颗粒酶诱导的凋亡有关的caspase10等. 下游的各种效应酶包括caspase3, caspase6, caspase7等. Cottlob et al[13]用含HBV x基因的质粒PCMV-X/F微注射或转染给REV2细胞或肝癌细胞, 发现他可以通过抑制caspase3而抑制细胞凋亡, 其抑制作用可被抗-HBx阻断.
Elmore et al[14]发现, X蛋白可以同p53形成复合物, 有效抑制p53介导的细胞凋亡, 从而为表达该病毒整合基因的肝细胞提供克隆选择优势, 导致肝细胞癌变.其可能机制是X蛋白使p53对Fas的正调控失效, 使应凋亡的肝细胞不能凋亡. p53与ERCC3结合是诱导细胞凋亡的机制之一. p53-HBX结合可使p53与ERCC3结合能力大大下降, 影响细胞凋亡. 将HBx与p53质粒一起微注射到人原代纤维瘤细胞核内, 24 h后可观察到p53表达水平并未由于HBx的存在而受影响, 但凋亡细胞从单独注射p53的19%降到1%, 这可能与HBx抑制p53下游基因p21的表达有关. Huo et al[15]研究发现, 突变后的HBx仍具有抑制p53介导的细胞凋亡的作用. 另有报道HBx突变后失去了其促凋亡活性[16], 因此HBx基因突变引起的对细胞凋亡的调节变化可能在HCC的发生发展中起重要作用. Lee et al[17]研究发现, HBx并不是通过使p53失活而抑制细胞凋亡的, 而是通过HBx-PI3K-Akt-Bad途径和caspase3的失活来实现的.Diao et al[12]也发现将HBx转入不表达P53的DP-16仍能抑制Fas介导的细胞凋亡. 这说明HBx对细胞凋亡的抑制作用至少部分是经由非p53依赖途径的.
NF-kB是真核细胞转录因子Rel蛋白质家族成员.Rel蛋白质家族成员包括p50/p105, p52/p100, Rel A(p65), Rel B和c-Rel等. 其中Rel A(p65), Rel B和c-Rel含有反式激活功能域, 能被HBx反式激活, 并参与对炎症反应、细胞增生与凋亡等的调控.研究发现大多数激活的NF-kB表现为抗凋亡 [18-22]. HBx能激活包括Rel A(p65), c-Rel, p52, p50等各种形式的NF-kB, 使NF-kB从胞质易位至核内, 作用于不同的靶基因, 从而抑制细胞凋亡[18,23-25]. Su et al[18]研究发现, 用大量IkBa抑制各种形式的NF-kB能增强HBx的促凋亡作用, 认为HBx在激活各种形式NF-kB的同时掩盖了其本身的促凋亡作用.
3.1.1 Fas-FasL死亡受体途径: Fas-FasL途径是细胞凋亡最重要的途径之一. 靶细胞表面的Fas与FasL结合, 诱导Fas分子三聚体化, 形成由Fas/FADD(Fas相关蛋白)/pro-caspase-8组成的死亡诱导信号复合物(DISC), pro-caspase-8活化, 继而激活下游的pro-caspase, 再通过一系列caspases(半胱-天冬氨酸蛋白酶)的级联激活反应诱导凋亡的发生. 有证据表明, HBV感染的肝细胞表面Fas蛋白表达增加[32]. 研究发现HBx可增强肝癌细胞中FasL 的表达, 其机制包括上调IL-18的表达和增强Egr-2 和 Egr-3(early growth response factor)的转录活性等[33-35]. 因此, HBx可能通过上调肝细胞表面Fas及FasL的表达, 加强死亡信号而通过Fas-FasL死亡受体途径促进表面表达Fas的肝细胞凋亡. 但是, Wang et al[36]认为HBx诱导Fas/FasL的表达并不能作为肝癌细胞凋亡的可靠标志. 此外, FasL表达的增高能促进表达Fas的T细胞凋亡, 这是肝癌细胞逃脱机体免疫监视的重要机制之一.
3.1.2 TNF死亡受体途径: TNF途径是细胞凋亡的另一重要途径.TNF-α与TNFR结合形成死亡诱导信号复合物(DISC), 后者募集无活性的caspase-8前体或FLICE, 使其裂解成活性形式, caspase-8启动下游caspase的级联激活导致靶细胞的凋亡. c-FLIP为细胞FLICE抑制蛋白, 是DISC最重要的调节因子. c-FLIP的稳定表达能保护细胞免受Fas, TNF和TRAIL(TNF相关凋亡诱导配体)受体等诱导的凋亡[37-39].Kim et al[40]研究发现, HBx能与c-FLIP的死亡效应区域1(DED1)结合形成复合体, 从而阻断了c-FLIP的抑凋亡作用, 使细胞对凋亡信号敏感. 因此, HBx能通过DISC相关途径直接干预死亡信号而诱导凋亡, 而c-FLIP是其最重要的靶位.此外, 他们还发现当用TNF-α和Fas抗体处理细胞时, HBx的表达能使caspase-8 和caspase-3过度激活, 这种激活可能与细胞对凋亡信号的敏感性有关. 研究发现, TNF基因的启动子上有HBx反式激活的靶序列, 故HBx能上调TNF-α的表达[41]. HBx还能通过下调Sep蛋白的表达而提高TNF-α的浓度[42]并降低其敏感阈值[40], 从而在促凋亡中起协同作用. 但HBx即使在无TNF-α处理时也能诱导凋亡[2,4]. 因此上调TNF-α的表达并不是HBx促进肝细胞凋亡的主要途径.
3.1.3 线粒体死亡途径: 传统观点认为线粒体内膜是产生能量的主要位点, 而外膜仅是第二层"皮肤".近年来的研究揭示了线粒体外膜在细胞凋亡中的重要作用. 正常情况下, Bcl-2家族成员作用于线粒体外膜并维持其稳定性. 线粒体外膜的破坏可导致两种关键的细胞凋亡调节物(细胞色素C和线粒体因子Smac(又称Diablo))的渗出, 从而启动和促进凋亡的发生. 因此, HBx可能通过对Bcl-2家族成员的调节而经由该途径诱导和促进凋亡[43-44]. 研究发现HBx定位于线粒体[45], 能直接作用于线粒体, 引起线粒体聚集和膜电位的丢失而引发线粒体依赖性的细胞凋亡[5,46-47]. VDAC是线粒体膜上渗透转换孔复合体中的成分,能调节线粒体膜电位和细胞色素C的释放. HBx就是通过与VDAC相互作用而影响线粒体膜电位和细胞色素C的释放, 从而引导线粒体依赖性细胞凋亡的[46].
3.2.1 p53: p53是典型的抑癌基因, 其产物分野生型和突变型两种形式. 野生型p53诱导细胞凋亡, 而突变型p53则抑制细胞凋亡. Elmore et al[14]研究HBV与p53在细胞凋亡调节中的作用显示: HBV X的C端, 不依赖其反式激活活性, 在细胞质中与p53形成复合物, 部分防止其进入细胞核并能诱导凋亡. 目前研究认为HBx与p53之间的相互作用在HCC的发病中起重要作用, 而HBx与p53对凋亡的调控作用是其中最重要的机制之一. HBx促进肝细胞凋亡可经由p53依赖途径[9]和非p53依赖途径[2-3]两种不同途径. Chirillo et al[9]用MMTV-X表达质粒转染NIH-3T3细胞后, DNA合成增加, 培养48-72 h后, 60%的细胞死亡, 表明HBx可诱导细胞从G0期到S期, 并促进细胞凋亡. 他们还发现这些表达HBx的克隆对p53介导的细胞凋亡敏感性增加.由于依赖p53诱导细胞凋亡包括多种途径, HBx不可能阻断所有p53介导的凋亡途径, 以及p53基因突变体或p53蛋白的失活.因此p53的状态可能影响HBV感染的肝细胞中HBx诱导凋亡的结果. Lassus et al[48]和Chen et al[49]研究表明, 正常水平的p53具有抗凋亡作用, 而高表达的p53则促凋亡. 所以当p53表达处于正常水平时, HBx可能因拮抗p53的抗凋亡作用而表现为促凋亡[4]; 当p53的表达处于高水平时, HBx则拮抗p53的促凋亡作用而表现为抑凋亡[50]. 然而, HBx诱导和促进凋亡也可以是经由p53非依赖途径[2-3]. 因此, p53也只是HBx促进凋亡过程中的重要调节因子之一.
3.2.2 Bcl-2家族: Bcl-2家族蛋白是体内调控细胞生存与凋亡最重要的调节因子, 促凋亡蛋白和抑凋亡蛋白在细胞中的比例将决定细胞对死亡信号的反应及细胞的命运[51-53]. 他包括Bcl-2, Bax, Bid, Bcl-x, mcl-1等成员. 目前认为Bcl-2, Bcl-xL等为抑凋亡因子, Bax, Bid则促凋亡. Bcl-2是一种重要的凋亡抑制蛋白, 能抑制多种因素引起的凋亡. Terradillos et al[43]研究发现, HBx能消除Bcl-2对Fas引导的凋亡的抑制作用, 且这种作用与HBx的表达量有关. 在成年的HBx/Bcl-2双转基因鼠中, HBx的低水平表达使细胞恢复了对Fas诱导的肝损伤的敏感性. 但酵母双杂合体系分析显示, HBx并不与Bcl-2家族的任何成员直接结合, 而且HBx的表达并不影响Bcl-2在细胞中的表达, 也不能阻断其与线粒体膜的结合. 新近研究表明HBx定位于线粒体, 通过与电压依赖的阴离子通道VDAC3相互作用而改变其膜电位[46]; 而Bcl-2家族蛋白能与VDAC结合而调节细胞色素Ｃ的释放. 因此推测是VDAC3与HBx的相互作用引起线粒体形态变化, 从而减弱了Bcl-2对离子通道活性的调节作用. 当然, HBx也可能通过激活Bcl-2的自然抑制因子如Bax或BH3单一性Bcl-2家族成员而抵消Bcl-2的作用. 有研究发现在未分化的4pX-1细胞中, HBx能促进Bax的表达[44]. 也有研究表明, HBx能使Bid的表达减少而阻断细胞调亡[54]. 因此, HBx对Bid的调节作用可能也参与了其促进凋亡的复杂过程. 已知Fas诱导的凋亡与细胞色素C从线粒体释放到细胞质有关, 且Bcl-2能阻断细胞色素C的释放.Terradillos et al[43]发现HBx能解除Bcl-2对Fas作用后的细胞中细胞色素C的释放和caspase-3活性的抑制作用.因此, 在Fas诱导的凋亡中, HBx可能是通过不被Bcl-2阻断的途径来激活细胞色素C的转运和caspase-3前体的裂解, 从而起到促进细胞凋亡的作用. Schuster et al[55]则发现共转染凋亡抑制物crmA和 p35不会影响HBx的促凋亡活性, 因此认为HBx可能是通过特异性激活Bcl-2敏感性途径来诱导和促进细胞凋亡的.
3.2.3 C-myc: c-myc属原癌基因. 他对细胞具有双重作用: (1)参与细胞的增生、转化. (2)促进或诱导细胞凋亡的发生. C-myc的表达使细胞进入细胞周期, 若在同时存在其他细胞因子的情况下, 则细胞存活, 增生, 否则发生凋亡. HBx能诱导某些细胞系中Myc基因的表达[9,56].而C-myc能使经TNF-α或其他因子处理的细胞对凋亡信号的敏感性增加或与其他促凋亡因子协同作用而促进细胞凋亡[57-59]. Chirillo et al[9]在X基因促进p53诱导细胞凋亡的研究中发现, 表达HBx的细胞中c-myc的表达显著增加, 认为C-myc可能也是HBx介导的凋亡中的重要递质. Su et al[6]用HBx表达载体转染HepG2和Chang肝细胞, 发现低水平表达的HBx能使细胞对TNF-α诱导的凋亡敏感性增加, 认为可能与激活C-myc和加强促分裂原活化蛋白激酶1(MAPKK1)有关.他们还发现HBx和C-myc共表达使WT 3T3细胞对TNF-α介导的凋亡敏感性显著增高, 且这种促凋亡作用超过了NF-kB的抗凋亡作用[18].
3.2.4 NF-kB: 如前述NF-kB多表现为抗凋亡, 但新近研究发现NF-kB具有促进细胞凋亡的作用[60-61]. 其机制可能是通过上调促凋亡基因的表达[62-63], 并与刺激信号的差异和细胞类型有关[64]. 因此, HBx诱导的NF-kB的激活可能也参与了HBx促进肝细胞凋亡的复杂过程.
3.2.5 其他: HBx反式激活iNOS的启动子能使NO产生增多, 导致肝细胞损伤[65-66].HBx的增强胞质中Ca2+信号的作用也可能是HBx诱导细胞凋亡的途径之一[67]. HBx能通过与UV-DDB相互作用而抑制受损DNA的修复并诱导凋亡[68-69]. 在感染早期, HBx能诱导TGF-β1的表达, 可能也是感染早期肝细胞凋亡增多的机制之一[70]. 此外, HBx还可与热休克蛋白60协同作用促进细胞凋亡[71].
总之, HBx可能是通过多途径, 多环节和多因子参与的复杂机制对肝细胞的凋亡进行调节, 可能因其自身的表达水平、HBV感染的阶段、细胞的类型(癌细胞或正常肝细胞)、细胞的内环境、细胞因子及干预因素等的不同而表现出促进或抑制凋亡两种不同的作用. 致力于HBx调节细胞凋亡的机制研究必将为包括肝细胞癌在内的HBV感染相关疾病的防治提供有利的理论依据.
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