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通讯作者:

景蓉蓉,E-mail:jrjr2020@163.com

中图分类号:R735.2

文献标识码:A

文章编号:1007-4368(2022)10-1476-06

DOI:10.7655/NYDXBNS20221021

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目录contents

    摘要

    胃癌是世界上最常见的恶性肿瘤之一。由于缺乏早期诊断标志物以及对现有治疗方案耐药,胃癌患者预后相对较差。新型细胞死亡方式的研究有望为胃癌的诊疗提供新靶点。目前胃癌中新型细胞死亡方式包括铁死亡、焦亡、坏死性凋亡、 自噬、溶酶体依赖性细胞死亡及NETosis,均属于程序性细胞死亡。本文介绍胃癌与这些新型细胞死亡方式间的相互关系及研究进展,以期为胃癌的诊断和靶向治疗提供理论依据和研究方向。

    Abstract

    Gastric cancer is one of the most common malignant tumor in the world. The prognosis is relatively poor due to the lack of early diagnostic markers and drug resistance to existing treatment options. The study of novel methods of cell death is expected to provide new targets for the diagnosis and treatment of gastric cancer. At present,novel cell death methods in gastric cancer include ferroptosis,pyroptosis,necroptosis,autophagy,lysosome - dependent cell death and NETosis,all of which belong to programmed cell death. In order to provide theoretical bases and research directions for the diagnosis and targeted therapy of gastric cancer,this article reviews the relationships between gastric cancer and cell death methods.

    关键词

    细胞死亡胃癌诊断治疗临床应用

  • 胃癌是起源于胃黏膜上皮的恶性肿瘤,2020年全球有超100万例新发的病例,死亡人数达76.9万[1],占消化道恶性肿瘤的第2位。由于胃癌患者早期症状不明显,大多数在确诊时已是晚期,因此胃癌的早期诊断仍是严峻的挑战。近年来,随着治疗方案的多样性,胃癌患者预后情况得到改善,但晚期胃癌患者也因多次化疗产生耐药而生存率降低。

  • 自1951年Gluchsman提出程序性细胞死亡 (programmed cell death,PCD)这一概念后,人们逐步了解PCD可能是癌症诊疗中关键的一部分。在过去几十年里,有11种PCD被发现,迄今为止,已在胃癌中鉴定出6种类型的PCD,包括铁死亡、焦亡、坏死性凋亡、自噬、溶酶体依赖性细胞死亡及NETosis。这几种新型细胞死亡方式参与了胃癌的发生发展,通过研究这些PCD途径将促进胃癌诊断和治疗策略的发展。

  • 1 新型细胞死亡方式在胃癌发生发展中的作用

  • 1.1 胃癌与铁死亡

  • 铁死亡是一种脂质过氧化物增加导致的铁依赖性细胞死亡。细胞内部铁离子异常积累和脂质过氧化被认为是铁死亡的诱因。核受体辅激活蛋白4介导的铁蛋白自噬导致细胞内铁水平和活性氧 (reactive oxygen species,ROS)增加,促进铁死亡[2]。然而这种调控铁含量介导的铁死亡现象仅在宫颈癌[3]、胰腺癌[4] 等肿瘤中被发现,在胃癌中尚未见报道。

  • 目前胃癌中调控铁死亡的研究多集中于氧化应激的调节,主要分为3类:①直接作用谷胱甘肽 (glutathione,GSH)系统;②调控多不饱和脂肪酸 (polyunsaturated fatty acids,PUFA)合成;③外泌体介导的铁死亡。最经典的方式属于GSH途径,其组成中的谷胱甘肽过氧化物酶4(glutathione peroxi⁃ dase4,GPX4)是铁死亡过程中必不可少的负调节剂。在胃癌细胞中半胱氨酸双加氧酶1的表达受抑可恢复GSH水平,提高GPX4活性,阻止ROS生成,抑制铁死亡[5]。脂质代谢在铁死亡中起关键作用,如胃癌中高水平的花生四烯酸和肾上腺素酸促进PUFA的合成,后者诱导脂质过氧化,激活铁死亡[6]。相反,Zhang等[7] 发现硬脂酰辅酶A去饱和酶1能将饱和脂肪酸转化为单不饱和脂肪酸,加速胃癌细胞增殖并抑制铁死亡。此外,癌症相关成纤维细胞衍生的外泌体[8] 能调节胃癌细胞中花生四烯酸脂氧合酶15表达,引起脂质ROS变化从而调控铁死亡和肿瘤进展。外泌体中的lncFERO通过调节异质核核糖核蛋白A1和泛素特异蛋白酶7,抑制顺铂和紫杉醇处理的胃癌细胞铁死亡,从而促使肿瘤发展[7]。可见通过诱导胃癌细胞铁死亡,抑制肿瘤细胞增长、提高治疗敏感性,可为开发胃癌诊疗新策略提供新思路。

  • 1.2 胃癌与焦亡

  • 焦亡也被称为细胞的炎性坏死,是一种重要的自然免疫反应。Brennan等[9]证实沙门氏菌通过caspase⁃1的促炎作用引发非特异性细胞膜渗漏,诱导细胞死亡,至此揭开焦亡研究的序幕。之后研究表明,焦亡是由炎症小体介导切割包括消皮素D(gasdermin D,GSDMD)在内的多种Gasdermin家族成员的PCD。在胃癌细胞SGC⁃7901和MKN⁃ 45中,GSDMD表达低于正常胃上皮细胞,低表达GSDMD导致其被切割释放出的N端片段减少,抑制后者与脂膜结合形成孔状结构,从而加速细胞周期,抑制焦亡促进细胞增殖与恶化[10]。除了GSDMD还有其他Gasdermin分子也参与焦亡。Wang等[11] 研究表明,切割的GSDME能导致5⁃氟脲嘧啶处理的胃癌细胞发生焦亡。Caspase家族作为Gasdermin必需的上游活化信号在焦亡中也发挥关键作用,其中切割GSDMD的有经典通路的Caspase⁃1和非经典通路的Caspase ⁃4/5/11,切割GSDME的Caspase ⁃3/8[12]。含NLR家族Pyrin域蛋白3(NLR family pyrin domain containing protein 3,NLRP3)具有激活Caspase⁃1并诱导细胞焦亡的潜力。lncRNA ADAMTS9⁃AS2通过下调miR⁃223⁃3p激活NLRP3炎性体,使顺铂耐药的胃癌细胞Caspase⁃1活性增加,后者对IL⁃1β和IL⁃18的前体进行切割并激活IL⁃1β和IL⁃18,诱导焦亡[13]。此外,NLRP3功能易受外界物质或炎性体激活剂宿主分子的刺激,从而被激活。如幽门螺杆菌分泌的CagA蛋白[14] 可激活NLRP3炎性体引起焦亡,产生大量成熟的IL⁃1β,影响胃癌的发生发展。因此,深入研究细胞焦亡与胃癌之间的联系,可为其在胃癌诊疗中的潜在价值提供研究方向。

  • 1.3 胃癌与坏死性凋亡

  • 坏死性凋亡是由细胞外刺激触发的死亡方式,这会引起受体相互作用蛋白激酶(receptor⁃ interacting protein kinase,RIPK)磷酸化,导致混合系列蛋白激酶样结构域(mixed lineage kinase domain ⁃ like,MLKL)募集。这种磷酸化使MLKL裂解质膜,导致损伤相关分子模式分泌。坏死性凋亡主要是依靠RIPK1和RIPK3的激活[15]。Guo等[16] 证实具有抗肿瘤活性的celastrol增加RIP1和RIP3的磷酸化水平,导致胃癌细胞坏死性凋亡,而抑制RIPK1活性的小分子Necrostatin⁃1可以减轻这种细胞的死亡效应。RIPK3是MLKL磷酸化激活坏死小体的关键成分,而MLKL是坏死性凋亡的主要执行者。与正常组织相比,胃癌组织中MLKL mRNA水平显著降低,MLKL介导的细胞坏死性凋亡能力降低[17]。因此,RIP1⁃RIP3⁃MLKL激活坏死性凋亡抑制癌细胞增殖,这为胃癌靶向非凋亡细胞死亡途径的诊疗开辟了新道路。

  • 1.4 胃癌与自噬

  • 自噬是一个连续的过程,由细胞膜吞噬自身的细胞质蛋白或细胞器形成的自噬体引发。其调控主要依赖于mTOR途径,包括PI3K⁃AKT⁃mTOR[18] 和AMPK⁃TSC1/2⁃mTOR等信号通路。在红景天苷诱导的胃癌AGS细胞中有自噬体形成,并且反映自噬水平蛋白质之一的LC3⁃Ⅱ表达增高。研究也表明PI3K⁃AKT⁃mTOR信号参与红景天苷诱导的胃癌自噬[18]。Kabeya等[19] 证明氧化应激也可诱导自噬,晚期胃癌二线治疗药伊立替康(irinotecan,IRI) 以浓度和时间依赖性方式上调LC3⁃Ⅱ。透射电镜分析显示,IRI加速自噬体形成,但受到3⁃MA等自噬抑制剂的影响。Zhu等[20] 发现ROS通过应激活化蛋白激酶和p38⁃MAPK途径介导IRI诱导的胃癌自噬和生长抑制。此外,自噬与程序性死亡配体1(programmed death⁃ligand 1,PD⁃L1)之间存在着新联系。自噬诱导剂雷帕霉素处理的胃癌细胞高表达LC3B⁃Ⅱ并使另一个自噬相关标志物p62/SQSTM1和PD⁃L1降低[21],表明雷帕霉素诱导自噬降低胃癌中PD⁃L1蛋白水平。总之,激活胃癌细胞中的自噬通路可以促进细胞死亡,同时能够为缓解耐药现象,增强化疗效果提供理论依据。

  • 1.5 胃癌与溶酶体依赖性细胞死亡

  • 溶酶体依赖性细胞死亡主要是通过溶酶体膜通透性(lysosomal membrane permeability,LMP)的变化来实现的。当LMP增加时,溶酶体中组织蛋白酶B和组织蛋白酶D的释放会引发溶酶体依赖性细胞死亡。组织蛋白酶抑制剂在许多情况下可以部分抑制由LMP介导的细胞死亡,如NF ⁃κB通路的Spi2A[22]。相反,信号转导与转录激活因子3和p53蛋白上调组织蛋白酶B、L和D的水平,后者充当蛋白酶促使细胞死亡。在用柚皮苷处理的AGS细胞中,作为溶酶体标志物的溶酶体相关膜蛋白1荧光强度显著增强,组织蛋白酶D酶原蛋白水平显著降低,重链组织蛋白酶D表达显著增加,促使柚皮苷诱导LMP激活溶酶体依赖性细胞死亡,抑制癌细胞增殖[23]。这种PCD是通过作用LMP,促进溶酶体释放组织蛋白酶,达到抑制细胞增殖目的,为胃癌的治疗提供一条新路径。

  • 1.6 胃癌与其他程序性细胞死亡方式的关系

  • NETosis是由中性粒细胞介导的反应。中性粒细胞胞外诱捕网(neutrophil extracellular trap,NET) 将染色质、组蛋白、颗粒和细胞质成分挤压在一起,再与入侵的微生物结合,并以高浓度的抑菌作用杀死细菌[24]。此前,Rayes等[25] 证实胃癌中NET水平升高,高水平的NET预示患者已处于癌症晚期,并且中性粒细胞诱导的NETosis能促进胃癌细胞的转移。因此,抑制NETosis可有效控制肿瘤的转移,为NETosis在胃癌治疗方面提供研究价值。另外,由多聚二磷酸腺苷核糖聚合酶⁃1介导的parthanatos、通过活细胞入侵同种细胞的entosis、由ROS和Kelch样ECH关联蛋白1介导的oxeiptosis以及依赖碱性细胞内环境的碱死亡,这4种PCD在胃癌方面的研究知之甚少。虽然每种细胞死亡方式都有其自身的机制,但它们并不是独立的个体,彼此之间仍然有着联系,如ROS是铁死亡过程中不可缺少的组成部分,同时能够参与坏死性凋亡和细胞焦亡。LMP不仅参与溶酶体依赖性细胞死亡,而且在自噬、坏死性凋亡和铁死亡的诱导下放大细胞死亡信号,提高细胞死亡的复杂性。除了新型细胞死亡方式之间存在联系外,与经典的PCD如凋亡之间亦存在关系。凋亡是一种由基因控制有序的细胞死亡方式,分为由膜受体(肿瘤坏死因子受体家族和死亡受体家族等)介导的外源性途径和由线粒体外膜通透性启动的内源性途径两种方式。胃癌细胞中高水平的ROS也可通过内质网应激和线粒体功能障碍诱导细胞凋亡[26]。此外,Caspase⁃3不仅能切割GSDME引起焦亡,而且可协同Caspase⁃9诱导细胞凋亡,但是凋亡不会引起炎症反应且无溶血现象。

  • 1.7 新型细胞死亡方式的检测方法

  • PCD作为机体多种免疫炎性疾病和癌症等病理生理过程的重要参与者,检测其发生发展具有重要临床意义。表1列举这几种细胞死亡方式的常用检测方法。

  • 2 新型细胞死亡方式相关生物标志物在胃癌诊断中的应用

  • 目前胃癌的诊断方法主要依靠胃镜检查与组织病理学方法,但其属于有创检查且无法实时监测。此外辅助诊断胃癌的血清学方法亦存在灵敏度和特异度较差的缺陷。因此,可以通过探究胃癌中的新型细胞死亡方式,找寻新的生物标志物,为胃癌的诊断提供新方法。

  • 硬脂酰辅酶A去饱和酶1 [27] 作为铁死亡负向调节因子被证明是胃癌的致癌基因,在93例胃癌病例中表达上调并且与TNM分期和远处转移显著相关,有望作为胃癌早期的生物标志物。Feng等[28] 阐明通过AMPK⁃mTOR途径诱导自噬的三结构域蛋白14在胃癌组织和细胞中稳定上调,是胃癌辅助诊断的指标。目前化疗药物已被广泛应用于胃癌的治疗,但长期化疗所导致的获得性耐药也是不可避免的,因此缓解化疗耐药至关重要。Peng等[29] 发现circCULN2在胃癌组织中表达较低,ROC曲线下面积为0.79,同时circCULN2通过miR⁃142⁃3p⁃ROCK2轴抑制顺铂耐药的胃癌细胞自噬,提示circCULN2有望成为胃癌诊疗的关键点[29]。抑制自噬的lncHAGLROS在胃癌中水平增高且与肿瘤浸润深度和TNM分期呈正相关,可用来反映胃癌患者的预后。另外,perilipin2被证明能调节脂质代谢从而调控铁死亡,并且在胃癌组织中明显上调[30],为其成为胃癌潜在预后生物标志物奠定了理论基础。另外,外泌体中circ PVT1和miR⁃423⁃3p在胃癌患者血清中呈高表达趋势,两者都可通过自噬途径调控细胞增殖,为非侵入性胃癌诊断生物标志物开辟道路。目前,越来越多的分子被证实在胃癌发生发展中发挥调控新型细胞死亡方式的作用,这为胃癌的诊断提供了新途径。

  • 表1 程序性细胞死亡方式检测指标

  • Table1 Detection indicators of programmed cell death

  • 3 新型细胞死亡方式在胃癌治疗中的应用

  • 研究表明与新型细胞死亡方式相关的药物已逐步应用于胃癌的治疗。最新报告发现,新型多靶向治疗肿瘤的多激酶抑制剂索拉菲尼在治疗癌症过程易发生耐药。敲低胃癌细胞中sirtuins 6抑制Nrf2信号通路,促进索拉菲尼诱导的铁死亡,从而增强药物治疗的敏感性[31]。CD44突变体在胃癌中依赖xCT通路促进GSH合成,抑制ROS介导的铁死亡,增强其对抗癌药物顺铂和多西他赛的抗性[32]。近期研究表明丹参酮ⅡA、猕猴桃根及大黄素甲醚8⁃O⁃β⁃吡喃葡萄糖苷等中药和作为局部麻醉剂的左旋布比卡因分别靶向不同的铁死亡途径从而调控胃癌发展。

  • 在增强胃癌药物疗效方面,新型细胞死亡方式也发挥重要作用,如化疗药物5⁃氟脲嘧啶和BIX⁃ 01294联合顺铂都能通过Caspase⁃3/GSDME通路调控焦亡,增强其在胃癌化疗中的效果[11]。曲妥珠单抗emtansine和自噬抑制剂联合应用促进前者进入溶酶体释放出emtansine,增强人表皮生长因子受体2阳性胃癌的治疗效果[33]。另外,抗肿瘤血管生成的celastrol和新合成的抗癌药物HUHS1015激活RIP1和RIP3,后者促进MLKL从细胞质到质膜的翻译,导致胃癌细胞的坏死性凋亡[16]。樱黄素在胃癌中也能激活RIPK3复合物,通过JNK导致线粒体ROS水平增加触发坏死性凋亡。除此之外,氟西汀通过坏死性凋亡增强紫杉醇对胃癌的化疗效果。红景天苷、甲基黄嘌呤衍生物(如咖啡因和茶碱)和小檗碱也分别通过PI3K⁃AKT⁃mTOR通路和MAPK通路促进胃癌中的自噬,调节肿瘤发展[18]。Peng等[34] 发现对成纤维细胞生长因子受体1抑制剂耐药的胃癌细胞可通过AMPK⁃mTOR通路诱导自噬,为对成纤维细胞生长因子受体抑制剂耐药的患者提供新的治疗策略。由此,这些新型细胞死亡方式在胃癌发生发展过程中的作用机制对探索治疗胃癌的新方法具有良好的参考价值。

  • 4 总结与展望

  • 胃癌的诊治仍然面临巨大的挑战,PCD在胃癌的发病机制中起着重要作用。虽然在动物模型和细胞培养中通过诱导PCD发生,胃癌进展得到明显抑制,但是这些方式还未通过临床验证。再者,铁死亡仍然缺乏特异性标志物,加上它在不同环境中的复杂性,如p53或Ras突变癌细胞,是铁死亡投入临床应用的挑战。另外,焦亡和坏死性凋亡募集的炎症细胞可能会促血管生成和癌症侵袭,产生免疫抑制性肿瘤微环境,因此应尽量避免能导致癌症恶化的炎性反应。同样,在癌症进展早期,自噬可充当肿瘤抑制因子,而在后期阶段,它会促进肿瘤对治疗的抵抗力,所以对抗化疗耐药依旧是治疗的重中之重。最后,由于人体内不可直接区分细胞死亡类型,与PCD相关的无创性液体活检指标有待进一步开发。随着药物开发和使用的多样性,靶向程序性死亡途径的药物可以广泛应用于癌症治疗。因此,进一步探索新型细胞死亡方式在胃癌发生发展中的作用,可对疾病早期诊断提供实验依据,并为胃癌患者选择合适的治疗方案,改善预后提供理论基础。

  • 参考文献

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    • [2] GAO M,MONIAN P,PAN Q,et al.Ferroptosis is an au⁃ tophagic cell death process[J].Cell Res,2016,26(9):1021-1032

    • [3] GRYZIK M,ASPERTI M,DENARDO A,et al.NCOA4⁃ mediated ferritinophagy promotes ferroptosis induced by erastin,but not by RSL3 in HeLa cells[J].Biochim Bio⁃ phys Acta Mol Cell Res,2021,1868(2):118913

    • [4] HOU W,XIE Y,SONG X,et al.Autophagy promotes fer⁃ roptosis by degradation of ferritin[J].Autophagy,2016,12(8):1425-1428

    • [5] HAO S,YU J,HE W,et al.Cysteine dioxygenase 1 medi⁃ ates erastin ⁃induced ferroptosis in human gastric cancer cells[J].Neoplasia,2017,19(12):1022-1032

    • [6] LEE J Y,NAM M,SON H Y,et al.Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivi⁃ ty in gastric cancer[J].Proc Natl Acad Sci U S A,2020,117(51):32433-32442

    • [7] ZHANG H,WANG M,HE Y,et al.Chemotoxicity ⁃ in⁃ duced exosomal lncFERO regulates ferroptosis and stem⁃ ness in gastric cancer stem cells[J].Cell Death Dis,2021,12(12):1116

    • [8] ZHANG H,DENG T,LIU R,et al.CAF secreted miR ⁃ 522 suppresses ferroptosis and promotes acquired chemo⁃ resistance in gastric cancer[J].Mol Cancer,2020,19(1):43

    • [9] BRENNAN M A,COOKSON B T.Salmonella induces macrophage death by caspase ⁃ 1⁃ dependent necrosis[J].Mol Microbiol,2000,38(1):31-40

    • [10] WANG W J,CHEN D,JIANG M Z,et al.Downregulation of gasdermin D promotes gastric cancer proliferation by regulating cell cycle⁃related proteins[J].J Dig Dis,2018,19(2):74-83

    • [11] WANG Y B,YIN B,LI D N,et al.GSDME mediates cas⁃ pase ⁃ 3 ⁃ dependent pyroptosis in gastric cancer[J].Bio⁃ chem Biophys Res Commun,2018,495(1):1418-1425

    • [12] 胡颖超,杨硕.细胞焦亡的研究进展[J].南京医科大学学报(自然科学版),2021,41(8):1245-1251

    • [13] REN N,JIANG T,WANG C,et al.LncRNA ADAMTS9⁃ AS2 inhibits gastric cancer(GC)development and sensi⁃ tizes chemoresistant GC cells to cisplatin by regulating miR⁃223⁃3p/NLRP3 axis[J].Aging(Albany NY),2020,12(11):11025-11041

    • [14] ZHANG X,LI C,CHEN D,et al.H.pylori CagA activates the NLRP3 inflammasome to promote gastric cancer cell migration and invasion[J].Inflamm Res,2022,71(1):141-155

    • [15] LIU Y,LIU T,LEI T,et al.RIP1/RIP3⁃regulated necrop⁃ tosis as a target for multifaceted disease therapy(Review)[J].Int J Mol Med,2019,44(3):771-786

    • [16] GUO D,ZHANG W,YANG H,et al.Celastrol induces necroptosis and ameliorates inflammation via targeting bi⁃ glycan in human gastric carcinoma[J].Int J Mol Sci,2019,20(22):E5716

    • [17] SUN W,YU W,SHEN L,et al.MLKL is a potential prog⁃ nostic marker in gastric cancer[J].Oncol Lett,2019,18(4):3830-3836

    • [18] RONG L,LI Z,LENG X,et al.Salidroside induces apop⁃ tosis and protective autophagy in human gastric cancer AGS cells through the PI3K/Akt/mTOR pathway[J].Biomed Pharmacother,2020,122:109726

    • [19] KABEYA Y,MIZUSHIMA N,UENO T,et al.LC3,a mammalian homologue of yeast Apg8p,is localized in au⁃ tophagosome membranes after processing[J].EMBO J,2000,19(21):5720-5728

    • [20] ZHU Q,GUO Y,CHEN S,et al.Irinotecan induces au⁃ tophagy ⁃ dependent apoptosis and positively regulates ROS ⁃ related JNK ⁃ and P38 ⁃ MAPK pathways in gastric cancer cells[J].Onco Targets Ther,2020,13:2807-2817

    • [21] WANG X,WU W K K,GAO J,et al.Autophagy inhibi⁃ tion enhances PD ⁃ L1 expression in gastric cancer[J].J Exp Clin Cancer Res,2019,38(1):140

    • [22] LIU N,RAJA S M,ZAZZERONI F,et al.NF⁃kappaB pro⁃tects from the lysosomal pathway of cell death[J].EMBO J,2003,22(19):5313-5322

    • [23] RAHA S,KIM S,LEE H,et al.Naringin induces lysosom⁃ al permeabilization and autophagy cell death in AGS gas⁃ tric cancer cells[J].Am J Chin Med,2020,48(3):679-702

    • [24] DE BONT C M,BOELENS W C,PRUIJN G J M.NETo⁃ sis,complement,and coagulation:a triangular relationship [J].Cell Mol Immunol,2019,16(1):19-27

    • [25] RAYES R F,MOUHANNA J G,NICOLAU I,et al.Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects[J].JCI Insight,2019,5:128008

    • [26] CHEN X,ZHAO Y,LUO W,et al.Celastrol induces ROS⁃ mediated apoptosis via directly targeting peroxiredoxin ⁃ 2 in gastric cancer cells[J].Theranostics,2020,10(22):10290-10308

    • [27] WANG C,SHI M,JI J,et al.Stearoyl ⁃CoA desaturase 1(SCD1)facilitates the growth and anti⁃ferroptosis of gas⁃ tric cancer cells and predicts poor prognosis of gastric cancer[J].Aging(Albany NY),2020,12(15):15374-15391

    • [28] XIAO F,OUYANG B,ZOU J,et al.Trim14 promotes au⁃ tophagy and chemotherapy resistance of gastric cancer cells by regulating AMPK/mTOR pathway[J].Drug Dev Res,2020,81(5):544-550

    • [29] PENG L,SANG H,WEI S,et al.circCUL2 regulates gas⁃ tric cancer malignant transformation and cisplatin resis⁃ tance by modulating autophagy activation via miR⁃142⁃3p/ROCK2[J].Mol Cancer,2020,19(1):156

    • [30] SUN X,YANG S,FENG X,et al.The modification of fer⁃ roptosis and abnormal lipometabolism through overexpres⁃ sion and knockdown of potential prognostic biomarker perilipin2 in gastric carcinoma[J].Gastric Cancer,2020,23(2):241-259

    • [31] CAI S,FU S,ZHANG W,et al.SIRT6 silencing over⁃ comes resistance to sorafenib by promoting ferroptosis in gastric cancer[J].Biochem Biophys Res Commun,2021,577:158-164

    • [32] ISHIMOTO T,NAGANO O,YAE T,et al.CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc ⁃ and thereby promotes tumor growth[J].Cancer Cell,2011,19(3):387-400

    • [33] ZHANG J,FAN J,ZENG X,et al.Targeting the autopha⁃ gy promoted antitumor effect of T⁃DM1 on HER2⁃positive gastric cancer[J].Cell Death Dis,2021,12(4):288

    • [34] PENG R,CHEN Y,WEI L,et al.Resistance to FGFR1⁃ targeted therapy leads to autophagy via TAK1/AMPK acti⁃ vation in gastric cancer[J].Gastric Cancer,2020,23(6):988-1002

  • 参考文献

    • [1] BRAY F,FERLAY J,SOERJOMATARAM I,et al.Glob⁃ al cancer statistics 2018:GLOBOCAN estimates of inci⁃ dence and mortality worldwide for 36 cancers in 185 countries[J].CA a Cancer J Clin,2018,68(6):394-424

    • [2] GAO M,MONIAN P,PAN Q,et al.Ferroptosis is an au⁃ tophagic cell death process[J].Cell Res,2016,26(9):1021-1032

    • [3] GRYZIK M,ASPERTI M,DENARDO A,et al.NCOA4⁃ mediated ferritinophagy promotes ferroptosis induced by erastin,but not by RSL3 in HeLa cells[J].Biochim Bio⁃ phys Acta Mol Cell Res,2021,1868(2):118913

    • [4] HOU W,XIE Y,SONG X,et al.Autophagy promotes fer⁃ roptosis by degradation of ferritin[J].Autophagy,2016,12(8):1425-1428

    • [5] HAO S,YU J,HE W,et al.Cysteine dioxygenase 1 medi⁃ ates erastin ⁃induced ferroptosis in human gastric cancer cells[J].Neoplasia,2017,19(12):1022-1032

    • [6] LEE J Y,NAM M,SON H Y,et al.Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivi⁃ ty in gastric cancer[J].Proc Natl Acad Sci U S A,2020,117(51):32433-32442

    • [7] ZHANG H,WANG M,HE Y,et al.Chemotoxicity ⁃ in⁃ duced exosomal lncFERO regulates ferroptosis and stem⁃ ness in gastric cancer stem cells[J].Cell Death Dis,2021,12(12):1116

    • [8] ZHANG H,DENG T,LIU R,et al.CAF secreted miR ⁃ 522 suppresses ferroptosis and promotes acquired chemo⁃ resistance in gastric cancer[J].Mol Cancer,2020,19(1):43

    • [9] BRENNAN M A,COOKSON B T.Salmonella induces macrophage death by caspase ⁃ 1⁃ dependent necrosis[J].Mol Microbiol,2000,38(1):31-40

    • [10] WANG W J,CHEN D,JIANG M Z,et al.Downregulation of gasdermin D promotes gastric cancer proliferation by regulating cell cycle⁃related proteins[J].J Dig Dis,2018,19(2):74-83

    • [11] WANG Y B,YIN B,LI D N,et al.GSDME mediates cas⁃ pase ⁃ 3 ⁃ dependent pyroptosis in gastric cancer[J].Bio⁃ chem Biophys Res Commun,2018,495(1):1418-1425

    • [12] 胡颖超,杨硕.细胞焦亡的研究进展[J].南京医科大学学报(自然科学版),2021,41(8):1245-1251

    • [13] REN N,JIANG T,WANG C,et al.LncRNA ADAMTS9⁃ AS2 inhibits gastric cancer(GC)development and sensi⁃ tizes chemoresistant GC cells to cisplatin by regulating miR⁃223⁃3p/NLRP3 axis[J].Aging(Albany NY),2020,12(11):11025-11041

    • [14] ZHANG X,LI C,CHEN D,et al.H.pylori CagA activates the NLRP3 inflammasome to promote gastric cancer cell migration and invasion[J].Inflamm Res,2022,71(1):141-155

    • [15] LIU Y,LIU T,LEI T,et al.RIP1/RIP3⁃regulated necrop⁃ tosis as a target for multifaceted disease therapy(Review)[J].Int J Mol Med,2019,44(3):771-786

    • [16] GUO D,ZHANG W,YANG H,et al.Celastrol induces necroptosis and ameliorates inflammation via targeting bi⁃ glycan in human gastric carcinoma[J].Int J Mol Sci,2019,20(22):E5716

    • [17] SUN W,YU W,SHEN L,et al.MLKL is a potential prog⁃ nostic marker in gastric cancer[J].Oncol Lett,2019,18(4):3830-3836

    • [18] RONG L,LI Z,LENG X,et al.Salidroside induces apop⁃ tosis and protective autophagy in human gastric cancer AGS cells through the PI3K/Akt/mTOR pathway[J].Biomed Pharmacother,2020,122:109726

    • [19] KABEYA Y,MIZUSHIMA N,UENO T,et al.LC3,a mammalian homologue of yeast Apg8p,is localized in au⁃ tophagosome membranes after processing[J].EMBO J,2000,19(21):5720-5728

    • [20] ZHU Q,GUO Y,CHEN S,et al.Irinotecan induces au⁃ tophagy ⁃ dependent apoptosis and positively regulates ROS ⁃ related JNK ⁃ and P38 ⁃ MAPK pathways in gastric cancer cells[J].Onco Targets Ther,2020,13:2807-2817

    • [21] WANG X,WU W K K,GAO J,et al.Autophagy inhibi⁃ tion enhances PD ⁃ L1 expression in gastric cancer[J].J Exp Clin Cancer Res,2019,38(1):140

    • [22] LIU N,RAJA S M,ZAZZERONI F,et al.NF⁃kappaB pro⁃tects from the lysosomal pathway of cell death[J].EMBO J,2003,22(19):5313-5322

    • [23] RAHA S,KIM S,LEE H,et al.Naringin induces lysosom⁃ al permeabilization and autophagy cell death in AGS gas⁃ tric cancer cells[J].Am J Chin Med,2020,48(3):679-702

    • [24] DE BONT C M,BOELENS W C,PRUIJN G J M.NETo⁃ sis,complement,and coagulation:a triangular relationship [J].Cell Mol Immunol,2019,16(1):19-27

    • [25] RAYES R F,MOUHANNA J G,NICOLAU I,et al.Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects[J].JCI Insight,2019,5:128008

    • [26] CHEN X,ZHAO Y,LUO W,et al.Celastrol induces ROS⁃ mediated apoptosis via directly targeting peroxiredoxin ⁃ 2 in gastric cancer cells[J].Theranostics,2020,10(22):10290-10308

    • [27] WANG C,SHI M,JI J,et al.Stearoyl ⁃CoA desaturase 1(SCD1)facilitates the growth and anti⁃ferroptosis of gas⁃ tric cancer cells and predicts poor prognosis of gastric cancer[J].Aging(Albany NY),2020,12(15):15374-15391

    • [28] XIAO F,OUYANG B,ZOU J,et al.Trim14 promotes au⁃ tophagy and chemotherapy resistance of gastric cancer cells by regulating AMPK/mTOR pathway[J].Drug Dev Res,2020,81(5):544-550

    • [29] PENG L,SANG H,WEI S,et al.circCUL2 regulates gas⁃ tric cancer malignant transformation and cisplatin resis⁃ tance by modulating autophagy activation via miR⁃142⁃3p/ROCK2[J].Mol Cancer,2020,19(1):156

    • [30] SUN X,YANG S,FENG X,et al.The modification of fer⁃ roptosis and abnormal lipometabolism through overexpres⁃ sion and knockdown of potential prognostic biomarker perilipin2 in gastric carcinoma[J].Gastric Cancer,2020,23(2):241-259

    • [31] CAI S,FU S,ZHANG W,et al.SIRT6 silencing over⁃ comes resistance to sorafenib by promoting ferroptosis in gastric cancer[J].Biochem Biophys Res Commun,2021,577:158-164

    • [32] ISHIMOTO T,NAGANO O,YAE T,et al.CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc ⁃ and thereby promotes tumor growth[J].Cancer Cell,2011,19(3):387-400

    • [33] ZHANG J,FAN J,ZENG X,et al.Targeting the autopha⁃ gy promoted antitumor effect of T⁃DM1 on HER2⁃positive gastric cancer[J].Cell Death Dis,2021,12(4):288

    • [34] PENG R,CHEN Y,WEI L,et al.Resistance to FGFR1⁃ targeted therapy leads to autophagy via TAK1/AMPK acti⁃ vation in gastric cancer[J].Gastric Cancer,2020,23(6):988-1002

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