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细胞凋亡与增殖在幽门螺杆菌感染致胃癌中的重要作用

细胞凋亡与增殖在幽门螺杆菌感染致胃癌中的重要作用

世界华消化杂志 1999年第9期第7卷 特约评论

作者:夏华向 张贵水

单位:夏华向 张贵水 Department of Medicine, Nepean Hospital, The University of Sydney, Sysney, Australia;张贵水 中国湖北医科大学附属第二医院消化内科

关键词:胃肿瘤;螺杆菌感染;细胞凋亡;细胞增殖

  中国图书馆分类号 R?735.2

  Subject headings stomach neoplasms; Helicobacter infections; apoptosis; cell proliferation

  0 引言

  流行病学研究及动物实验已表明,幽门螺杆菌(Hp)感染是胃癌发生的因素之一[1,2]. 目前已提出许多致癌机制,其中一个重要机制是Hp刺激胃上皮细胞增殖及诱导胃上皮细胞凋亡[3]. Hp,特别是毒素相关蛋白A(CagA)阳性菌株感染与癌前病变如胃粘膜萎缩和肠上皮化生关系密切[4-8]. 在本期中,卢世云et al[9]的研究表明,Hp阳性的慢性浅表性胃炎患者胃上皮细胞增殖显著高于无胃粘膜病变及Hp阴性浅表性胃炎患者,而在癌前病变阶段Hp感染与非感染的患者胃上皮细胞增殖虽均高于无胃粘膜病变患者,但两组间并无显著差别,提示Hp主要在胃癌发生中起始动作用. 然而,许多问题尚待回答,譬如:Hp是如何刺激细胞增殖的?Hp感染是如何导致胃粘膜萎缩和肠上皮化生的?Hp在胃癌发生的始动以及进程中究竟起什么作用?最近一些研究表明,Hp诱导胃上皮细胞凋亡,而细胞凋亡的增加可进一步刺激胃上皮细胞增殖,同时可导致胃粘膜萎缩. 因而细胞凋亡在胃癌的发生中很可能起着重要作用[10,11]. 我们将探讨Hp诱导的细胞凋亡及其在胃癌发生中的重要性.

  1 Hp诱导胃上皮细胞凋亡

  Moss et al[12]首先报道,Hp阳性的十二指肠溃疡患者的胃上皮存在大量凋亡细胞,而Hp阴性的非溃疡性消化不良患者,凋亡细胞少见. 根除Hp后,细胞凋亡指数降为正常. 其他对不伴有胃粘膜萎缩,肠上皮化生,不典型增生以及胃癌的胃炎或消化性溃疡患者的一系列研究也得到类似结果[13-16]. Jones et al[17]观察到Hp感染的胃炎患儿比由非甾体类抗炎药等引起的继发性胃炎以及无胃炎对照组的胃上皮细胞凋亡指数高,但随着Hp的根除及胃炎的消退,凋亡指数下降. 体外研究表明,用活菌或死菌或超声粉碎的全细胞抗原孵育胃癌细胞系,可诱导凋亡发生[18,19]. 动物实验亦表明,用Hp接种小鼠,可使小鼠的胃上皮细胞凋亡指数增加[20,21].

  到目前为止,Hp诱导胃上皮细胞凋亡的机制尚未完全阐明. CagA不但与空泡毒素蛋白(VacA)的表达相关,而且是Hp DNA中编码某些疾病相关毒性因子并称为的“致病基因岛”的标志物[22]. 然而cagA基因的存在或VacA蛋白的表达似乎均与诱导凋亡无关. 许多研究表明,CagA阳性或阴性菌株均能诱导细胞凋亡[18,20,21]. Peek et al[23]报道CagA+菌株感染患者胃粘膜细胞凋亡指数比CagA-感染的为低,而与未感染群的凋亡指数相似. 这提示,CagA+菌株刺激胃粘膜细胞增殖的同时,凋亡细胞却无相应的增加,从而增加致癌的危险性. 有研究表明,细胞壁脂多糖干扰上皮细胞与细胞内基质蛋白之间的相互作用,并改变胃酸分泌[24,25]. 最近,有给小鼠胃饲Hp脂多糖后发现,不仅胃表皮层,而且深部腺体均出现大量的凋亡细胞,同时发现凋亡指数与急性炎症反应的程度成正相关[26]. Hp产生的尿素酶水解尿素形成氨与二氧化碳. 同时,Hp可激活中性粒细胞而产生大量的活性氧代谢产物. 其中,次氯酸与氨作用所形成的单氯胺与粘膜损害有关[27]. 最近一项体外研究表明,单氯胺可阻碍小鼠胃粘膜细胞系(RGM-1)生长,诱导其凋亡[28]. 另有研究提示Hp活性氮代谢物在胃癌发生中的作用[29]. 这些物质是由诱导型一氧化氮合酶合成的一氧化氮衍生. Hp感染使诱导性一氧化氮合酶得以表达,从而导致巨嗜细胞和中性粒细胞持续产生一氧化氮[13,14]. 内源性活性氮中间产物可造成DNA损伤,继而中断细胞周期或诱导凋亡.

  研究表明,由辅助T1细胞产生的某些细胞因子如肿瘤坏死因子α(TNF-α)和γ-干扰素(IFN-γ)可显著促进Hp诱导的凋亡[18,19,30,31],而另一些细胞因子如白介素10(IL-10)则可阻碍Hp诱导的细胞凋亡[32]. 目前对Hp诱导的细胞凋亡的基因机制还知之甚少. Jones et al[17]报道Hp感染的患儿胃窦上皮细胞野生型P53的表达增加. 然而,P53的集聚与细胞周期依赖性激酶抑制剂P21无相关性,提示在Hp感染过程中,P53蛋白可能诱导细胞凋亡,而不是中止细胞周期[17]. Kodama et al[33]给日本猴接种Hp后,发现3,4?a后P53的阳性表达率分别为50%及67%,而未接种的则无表达. 但由于没有提供组织学及凋亡等数据,因而无法评价P53染色阳性与凋亡和癌前病变的关系. 据报道,在细胞培养物中加入Hp后,除诱导凋亡外,还伴随着Bak(bcl-2相关杀伤基因)的表达增加,然而bcl-2家族其他成员几乎没有变化,此外,Hp阳性患者胃上皮细胞Bak的表达也增加[34]. 这些资料均提示Hp诱导细胞凋亡可能由Bak依赖性路径所介导.

  2 细胞凋亡与增殖

  一系列研究均表明,Hp感染患者胃上皮细胞增殖速度比正常对照组加快,根除Hp后细胞增殖速度下降[35-38],根除后如再感染Hp,原本下降的细胞增殖速度又恢复到治疗前的水平[39]. 尽管许多体外实验结果不一[18,40,41],但确有作者观察到,培养细胞经与Hp或Hp上清液培育后,其增殖速度加快[42]. 总之,Hp感染可加速细胞增殖与凋亡. 有证据表明,胃粘膜慢性感染本身不足以使胃上皮细胞更替加速,而Hp感染必不可少[38]. 因此,由Hp感染引起的促胃液素水平的增加,以及炎性反应中细胞因子与氧自由基的产生都可能刺激胃粘膜细胞的增殖[43]. 更重要的是,Hp诱导的细胞凋亡可能在细胞增殖中起重要作用[10,44]. 有结果显示,细胞凋亡是胃上皮细胞对Hp感染的初始反应[10,11,44]. 为了保持胃粘膜细胞总量,过量的细胞凋亡会诱发代偿性细胞增殖,一旦出现细胞过度增殖,那么,易受基因毒性损害及有“利他性”细胞死亡(凋亡的一种自我防御形式)倾向的分裂细胞比率增加. 一旦这种“利他性”机制失灵,那么,组织就可能出现无限制增殖[44].

  无癌前病变或癌变的患者Hp感染所诱导的凋亡和细胞增殖是可逆的. 继往研究表明,慢性萎缩性胃炎,肠化生,不典型增生和胃癌胃上皮细胞增殖加快,但它与胃内Hp感染无关,而且肠化生引起的过度增殖并不因Hp的根除而逆转[9,45,46]. 这似乎表明,Hp感染与慢性胃炎的过度增殖有关,但它不影响癌前病变或胃癌的上皮细胞增殖,进一步提示Hp感染在胃癌发展中起始动作用. 目前还不清楚肠化生,不典型增生及胃癌的凋亡增减是否与Hp感染有关,Hp根除后加速的凋亡是否可逆转.

  在Hp感染消失或根除情况下,肠化区域胃上皮过度增殖持续存在,可能与增殖过程的调节改变有关. 这种改变可能与肠化时所表现的基因变化有关[46]. 研究表明,细胞凋亡与增殖受大量在进化过程中保守癌基因和抑癌基因产物的调节. 某些产物如P53,C-myc, Rb和C-fos同时也参与细胞周期的调节,这提示细胞凋亡与增殖过程相互关联和影响[47].

  3 细胞凋亡与胃萎缩

  大量研究表明,Hp感染可引起部分胃萎缩[5-7]. 推测Hp持久地诱导大规模凋亡可导致胃腺体萎缩,并继而在少数可发展为肠化生,不典型增生和胃癌[11,48]. 由于腺体颈部是粘膜腺体和表皮细胞复制和增殖的部位,该部位粘膜腺体的凋亡尤为重要. 粘膜腺体的缺失(萎缩性胃炎的定义)可能是由于持续炎症所致的持久的腺体细胞凋亡而得不到及时更替所致[11]. 有证据表明,腺体颈部是炎症最集中的部位,而且在Hp感染后,此处凋亡达到较高水平[12,13].

  4 Hp诱导的凋亡在胃癌发生中的作用

  Hp在胃上皮的群集繁殖可释放出大量能损伤胃粘膜的酶(尿素酶,磷脂酶,过氧化物酶等)和VacA等. Hp感染可刺激中性粒细胞等产生大量的氧自由基,从而损害上皮细胞的DNA,后者导致大量细胞因子的释放,特别是T1辅助细胞释放出TNF-α,IFN-γ,加重粘膜的炎性及损伤. 上皮细胞受损,特别是DNA损伤,可诱发凋亡. 另一方面,Hp感染产生的许多分子如脂多糖等可直接诱发凋亡. 为了保持组织稳态,凋亡增加则进一步诱发细胞增殖. 细胞凋亡和增殖可持续存在,直到根除Hp使凋亡的刺激因素得到消除为止. 同时,长期Hp感染的直接作用和细胞凋亡易引起胃萎缩,进一步可发展为肠化生和不典型增生. 促进凋亡的基因(如p53,bcl-2一部分家族成员)或抑制凋亡的基因(如bcl-2一部分家族成员)在“高运转”状况下可能发生改变或突变. 这些状况包括:上皮细胞的过度增殖,感染及炎性的胃微环境中存在突变源,以及企图抑制增强的细胞凋亡和增殖. 然而,所改变的基因表达可能是细胞周期依赖性的,并不能控制增速的细胞更迭. 例如,突变型P53蛋白既不能诱导凋亡也不能抑制细胞生长,而Bcl-2的过度表达却能促进细胞增殖,最终细胞凋亡与增殖的平衡将向后者倾斜,这时,胃粘膜朝肿瘤方向发展也就不可避免.

  Correspondence to:Dr. Harry Hua-Xiang Xia, Department of Medicine, The University of Sydney, Nepean Hospital, P.O. Box 63, Penrith, NSW 2751, Australia

  Tel. +61-2-47242682 Fax. +61-2-47242614

  Email.xia@med.usyd.edu.au

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收稿日期 1999-08-10


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