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World Journal of Cancer Research
Vol. 13  No. 02 ( 2023 ), Article ID: 63919 , 7 pages
10.12677/WJCR.2023.132005

肝细胞癌相关内质网应激的研究进展

徐佳怡，吴亮

中国药科大学药物科学研究院，江苏 南京

收稿日期：2023年3月10日；录用日期：2023年4月1日；发布日期：2023年4月14日

摘要

内质网应激在癌症中具有多种调节作用。当mRNA翻译速率与蛋白折叠效率之间平衡被破坏，错误折叠或未折叠的蛋白质在内质网腔中的积累时，引起内质网应激，并触发未折叠蛋白质反应，以恢复蛋白质合成或者诱导细胞死亡。肝细胞癌是全球最常见和最致命的癌症之一，预后极差。内质网应激为肝细胞癌的关键因素，与肝细胞癌的发生和发展、耐药性和死亡调节密切相关，靶向内质网应激已成为潜在的抗肿瘤策略。本文结合近5年的相关文献，针对内质网应激对肝癌的影响进行概述。

关键词

肝细胞癌，内质网应激，未折叠蛋白反应，抗癌治疗，耐药

Research Progress of Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Jiayi Xu, Liang Wu

Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing Jiangsu

Received: Mar. 10th, 2023; accepted: Apr. 1st, 2023; published: Apr. 14th, 2023

ABSTRACT

ER stress was confirmed to be multiple regulators of cancer. When there are imbalances between the rate of mRNA translation and the efficiency of protein folding and unfolded or incompletely folded proteins accumulating in the ER, the cell experiences ER stress. This process triggers the unfolded protein response in order to restore protein synthesis or induce cell death. Hepatocellular carcinoma is one of the most common and deadly cancers worldwide with an extremely poor prognosis. ER stress has gradually been shown to be a major mechanism of hepatocellular carcinoma and was associated with tumorigenesis, development, drug resistance and cell death, targeting ER stress has emerged as a potential anti-tumor strategy. We searched for relevant publications in the last five years and present an overview of the current knowledge that links ER stress and HCC.

Keywords:Hepatocellular Carcinoma, Endoplasmic Reticulum Stress, Unfolded Protein Response, Anti-Cancer Therapy, Drug Resistance

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 肝细胞癌及其治疗

原发性肝癌为世界发病率第六的癌症 [1] ，其中肝细胞癌(Hepatocellular Carcinoma, HCC)占原发性肝癌的75%~85% [2] ，位居全球癌症死亡人数第三，其相对5年生存率仅约为18% [3] ，是仅次于胰腺癌的第二大致命性肿瘤 [1] 。肝细胞癌早期的治疗方案为局部治疗，虽然早期发现可提高患者的生存率，是现阶段改善治疗结果的关键，但大多数肝癌患者在诊断时就已经处于中晚期，此时患者则考虑全身化疗 [1] [3] [4] ，一般通过药物疗效来选择不同的推荐治疗方案，包括靶向疗法和免疫疗法 [3] 。然而，作为一线用药的索拉非尼患者中位生存期仅为12.3个月，尽管其他一线用药仑伐替尼、阿替利珠单抗联合贝伐珠单抗、阿替利珠单抗联合卡博替尼的疾病控制率超过70%，显示出良好的治疗效果，但中位生存率仍不超过20个月 [3] 。肝细胞癌复发和转移频繁，其潜在机制尚不完全清楚，亟需解决。

2. 内质网应激和未折叠蛋白反应

分泌蛋白的合成约占整个细胞蛋白合成的三分之一，内质网(Endoplasmic Reticulum, ER)负责细胞内几乎所有分泌蛋白的折叠 [5] 。当翻译速率与折叠效率之间平衡被破坏，ER上未折叠或错误折叠的蛋白质的累积，将导致内质网应激(Endoplasmic Reticulum Stress, ERS) [5] [6] 。细胞可以通过ER相关蛋白质降解(ERAD)降解它们，也可以通过未折叠的蛋白质反应(Unfolded Protein Response, UPR)来恢复正常的蛋白质稳态 [5] 。UPR是一种专门的信号通路，旨在维持蛋白质平衡，在ERS期间扩大ER蛋白折叠能力，降解错误折叠的蛋白质，并减少新蛋白的合成以减轻对ER的负荷 [4] 。其中ER应激传感器——肌醇需求蛋白1α (IRE1α)，激活转录因子6 (ATF6)和蛋白激酶RNA样内质网激酶(PERK)，这三种ER跨膜蛋白共同调节参与ER功能控制的数千个基因 [5] 。

2.1. IRE1α

IRE1α是一种I型跨膜蛋白，在ERS期间，ER伴侣Bip (又称GRP78)以更高的亲和力结合未折叠蛋白后，与IRE1α的管腔内部分解离，促进IRE1α二聚化和反式自磷酸化，激活IRE1α的核酸内切酶活性 [5] [6] 。ERS的水平影响IRE1α激活的程度，当ERS处于较低水平时，IRE1α从XBP1转录本中切除抑制性内含子，以产生活性蛋白XBP1s，XBP1s的转录靶标包括编码ER蛋白折叠、分泌、ER相关降解、ER生物发生和脂质合成功能的基因 [5] [6] [7] ，以缓解ERS。

当ERS长期且强烈时，磷酸化的IRE1α从同源二聚体转变为高阶低聚物，获得对XBP1 mRNA以外的其他RNA底物的亲和力，以降解ER表面的mRNA，被称为调节IRE1依赖性衰变(RIDD) [5] [6] [7] ，这一过程看似可减轻蛋白翻译的负荷，但可能进一步恶化ERS。IRE1α可直接切割促凋亡靶标的microRNA，如miR-17 [8] ，硫氧还蛋白相互作用蛋白(TXNIP)，导致其快速上调，以激活炎症小体及其半胱天冬酶-1依赖性致死途径 [7] 。另外，寡聚化的IRE1α还可以激活细胞凋亡信号调节激酶1 (ASK1)和c-Jun NH2-末端激酶(JNK)，p38和NF-κB途径，从而调节炎症，自噬和细胞凋亡 [6] [9] 。

2.2. PERK

PERK是另一种ER驻留的I型跨膜蛋白，与IRE1有着相似的激活机制。在ERS条件下，Bip从PERK的管腔内部分解离，随后PERK通过同源二聚化和自磷酸化激活，磷酸化真核翻译起始因子2α (eIF2α) [5] 。eIF2复合物是帽依赖性mRNA翻译过程中所需的GTP结合蛋白。它的功能为将Met-tRNA带到核糖体，因此eIF2α但一旦磷酸化，就会阻止eIF2-GTP-Met-tRNA三元复合物的结合，以减少全局mRNA的翻译，缓解未折叠蛋白的积累 [5] [8] 。PERK也可磷酸化核因子红系2相关因子2 (Nrf2)，改善细胞的氧化应激 [8] 。

虽然p-eIF2α可减少整体蛋白质合成，但它选择性地上调转录因子ATF4的非帽依赖型翻译 [8] 。ATF4转移到细胞核中并转录上调几种UPR靶基因，介导抗氧化反应以及氨基酸的合成和转运。ATF4上调的PPP1R15A (也称为GADD34)可与G-肌动蛋白和蛋白磷酸酶1 (PP1)组成复合物，使磷酸化eIF2α去磷酸化以恢复正常的翻译速率。另外，ATF4上调转录因子C/EBP同源蛋白(CHOP，也称为GADD153、DDIT3)，诱导相关基因(包括XBP1和ER伴侣)表达，使ER趋向稳态；高水平的CHOP可诱导生长停滞，抑制抗凋亡蛋白BCL-2的表达，并上调促凋亡BIM以触发线粒体依赖性凋亡途径的激活，以加速细胞死亡 [4] [5] [6] [7] [8] 。

2.3. ATF6

激活转录因子ATF6是一种II型ER跨膜蛋白。在ER应激期间，ATF6与BiP解离并离开ER转移到高尔基体中，通过位点1蛋白酶(S1P)和位点2蛋白酶(S2P)的切割，产生具有转录因子活性的胞质片段并转运至细胞核，以促进XBP1和参与ERAD的基因的表达。此外，ATF6和XBP1形成异二聚体以促进ERAD，在没有XBP1的情况下，ATF6促进脂质合成和内质网扩增 [10] 。ATF6信号通路主要介导适应性调节，很少在应激条件下促进细胞死亡，ATF6可能也有促凋亡靶标，但这些靶标尚未明确 [4] [5] [7] [11] 。

已知ERS在一系列疾病中起因果作用，包括肝癌。ERS与肝癌的发生发展、转移、免疫抑制和耐药性等有关 [4] [11] 。在这里，我们回顾了2018年到2023年的相关文献，将文献分为三大类，总结了近5年来ERS和肝癌的最新研究成果。

3. 内质网应激与肝细胞癌

3.1. ERS导致肝癌的发生发展

冠层同系物2 (Canopy homolog 2, CNPY2)是一种ER蛋白，在肝癌中表达上调，与肝癌患者的存活率呈负相关。CNPY2可增强PERK和IRE1α的活性，诱导 ATF4和CHOP表达，导致p53的抑制和细胞周期进展，敲除CNPY2可抑制小鼠由二乙基亚硝胺(DEN)诱导的HCC [12] 。暴露于全氟和多氟烷基物质(PFAS)是常见的有机污染物，可特异性地促进了肝癌细胞的存活，诱导TNFα和IL-6炎症标志物的表达，内源性活性氧(ROS)的产生，并激活UPR，伴随脂肪变性和纤维化标志物表达的上调 [13] 。Caudatin在体内减少由DEN诱导的大鼠肝结节的数量和大小，通过抑制ATF6、PERK/eIF2α/ATF4相关通路，减少毒性的累积 [14] 。

α-1抗胰蛋白酶缺乏症(AATD)与肝细胞癌的发生有关。变异型PI*Z (Glu342Lys)最常见，可导致α1-抗胰蛋白酶在内质网上异常积累，触发UPR，其中PERK和IRE1α分支受到抑制，而ATF6α分支保持活性，以促进肝细胞的存活 [15] 。

CD5-like (CD5L)在肝细胞癌中上调，可促进细胞增殖和集落形成，并防止顺铂诱导的细胞凋亡，其机制与激活肝细胞癌细胞中的UPR和自噬有关 [16] 。增强α-甘露糖苷酶样蛋白1 (EDEM1)的沉默可稳定ATF6蛋白，增强 ATF6转录活性，从而促进其适应性功能，有利于癌细胞生长 [17] 。UNC5家族是一类死亡受体(DRs)，可促进细胞凋亡，肝癌患者UNC5A表达较低，UPR可诱导的UNC5A翻译抑制，对肝癌发生发展有潜在的影响 [18] 。

对肝细胞癌患者的分析显示，高尔基蛋白73 (GP73)、GRP78的表达和肿瘤相关巨噬细胞(TAM)的密度呈正相关。ERS可增加GP73的细胞分泌，分泌的GP73引起邻近巨噬细胞的ERS并促进细胞释放细胞因子和趋化因子。在小鼠HCC模型中，下调GP73可降低TAM的密度，抑制肿瘤生长 [19] 。P2Y12受体是一种ADP响应性G蛋白偶联受体，P2Y12可由肝巨噬细胞表达，该受体通过诱导ERS介导巨噬细胞极化和功能，可能与炎症驱动的肝硬化和肝细胞癌有关 [20] 。

毛玻璃肝细胞(GGH)是慢性乙型肝炎病毒(HBV)感染的组织学标志，其在内质网中乙型肝炎表面抗原(HBsAg)过度积累，Bip染色增加，UPR的PERK途径激活，可能导致癌前表型的出现 [21] 。HBV的PreS基因突变可能引起病毒蛋白和颗粒的分泌缺陷，导致突变的HBsAg在内质网上积累，致使细胞处于UPR激活、钙超负荷、线粒体功能障碍，能量代谢受损，基因组不稳定的状态，促使肝纤维化以及肝癌的发生 [22] 。小表面抗原(SHBs)是HBV感染的肝细胞中表达最丰富的HBV蛋白，可诱导内质网ER应激，从而激活UPR信号传导以增加VEGFA表达和分泌，增强HCC细胞的血管生成能力 [23] 。上调基因克隆7 (URG7)是一种ER驻留蛋白，当存在HBxAg时表达增加，能够上调GRP78并下调CHOP的表达来缓解ER应激 [24] 。在Huh-7.5肝细胞的持续性HCV感染模型中，UPR传感器PERK通过NRF2/STAT3介导促生存信号，降低肝细胞核因子4α (HNF4A)的表达，导致肝脏特异性microRNA-122转录也显着降低，进而增加了HCC的风险 [25] 。

3.2. ERS导致肝癌的耐药

在肝细胞癌患者样本中，自噬相关蛋白Beclin1的表达与UPR途径蛋白(尤其是PERK)表达之间存在高度相关性，PERK和Beclin1联合表达往往处于疾病更晚期阶段。ER应激相关的自噬在细胞凋亡抵抗中起关键作用，低浓度的褪黑激素通过PERK-ATF4-Beclin1途径抑制自噬，增加了HCC对索拉非尼的敏感性 [26] 。lncRNA，ZFAS1 (ZNFX1反义RNA 1)可促进HCC转移，索拉非尼诱导PERK/ATF4依赖性ZFAS1表达，导致耐药，PERK/ATF抑制剂可以克服索拉非尼耐药 [27] 。UDP-葡萄糖6-脱氢酶(UGDH)通过调节未折叠的蛋白质反应降低索拉非尼的敏感性，联合UGDH可以显着提高索拉非尼的疗效 [28] 。

神经酰胺耐药癌细胞中的鞘脂代谢有利于外源性神经酰胺转化为促生存鞘脂，激活UPR，进一步启动自噬和可逆衰老样表型(SLP)，赋予癌细胞抗性 [29] 。

3.3. ERS导致肝癌细胞的死亡

含三方基序(TRIM)家族蛋白参与细胞蛋白质量调控，与许多疾病发生发展有关。TRIM25蛋白可响应肝癌细胞系中的ER应激，作为一种反馈机制，TRIM25的上调可改善氧化应激，促进ERAD，并减少UPR途径中的IRE1信号传导，敲低TRIM25可导致持续的ER应激并抑制肿瘤细胞的生长 [30] 。SHQ1是一种ERS反应基因，由ATF6和XBP1s调节。SHQ1与ER伴侣GRP78相互作用，促进PERK/IRE1α/ATF6的解离，导致未折叠蛋白反应(UPR)的超激活，从而诱导细胞凋亡。在患者的HCC组织显示SHQ1的表达显着降低，异种移植模型表明增加SHQ1水平可增强ERS诱导剂的抗肿瘤活性 [31] 。

3,3’-二吲哚甲烷(DIM)诱导ER应激并激活UPR反应，影响Bip，IRE1α，CHOP等关键指标的表达，诱导肝细胞凋亡，另外，DIM通过调节ERS介导的Smad 2/3途径抑制EMT来抑制Hep3B和Huh7细胞的肿瘤生长和转移 [32] 。HIV-1蛋白酶抑制剂前体RDD-19和RDD-142对肝癌细胞具有明显的细胞毒性，并可诱导持续性和剂量依赖性ERS [33] 。隐美二醇(Bkh126)可激活的UPR并沉默的孤儿核受体Nur77，Nur77可感知被激活的IRE1α-ASK1-JNK信号并转移到线粒体，导致线粒体膜电位的丧失，引起肝癌细胞死亡 [34] 。diTFPP是一种新型苯氧基酚化合物，与神经酰胺共同处理，可增加细胞的氧化应激和ERS，并抑制自噬体和溶酶体的融合，导致癌症细胞死亡 [29] 。UPR诱导剂(-)-Agelamide D可增强Hep3B细胞的辐射敏感性，增加PERK/eIF2α/ATF4的表达，降低集落数量并增加凋亡细胞死亡 [35] 。b-AP15是泛素特异性肽酶14 (USP14)的有效选择性抑制剂，可通过增强ER应激抑制肝癌细胞生长 [36] 。黄霉素通过激活ERS诱导人肝癌细胞凋亡，其中PERK/eIF-2α/ATF4轴变化最为显着 [37] 。ML324是一种组蛋白赖氨酸去甲基化酶4 (KDM4)的小分子特异性抑制剂，可通过ATF3/CHOP途径，上调死亡受体5 (DR5)的表达，诱导HCC细胞死亡 [38] 。真染色质组蛋白甲基转移酶II (EHMT2)介导组蛋白H3在H3K9处的二甲基化，使用EHMT2的化学抑制剂BIX-01294处理肝癌细胞系后，细胞凋亡、UPR等有关的基因被上调 [39] 。M6-1D4是靶向CD147的单克隆抗体，处理HepG2后显示细胞UPR激活，自噬体积累和细胞周期停滞，但没有典型的细胞凋亡相关特征，延长处理时间至24小时可导致肿瘤坏死性凋亡，这一途径可能与混合谱系激酶结构域样假激酶(MLKL)有关，并独立于丝氨酸/苏氨酸蛋白激酶(RIPK)磷酸化 [40] 。18β-甘草次酸(GA)抑制了各种HCC细胞系的增殖，引起细胞G0/G1停滞、凋亡和自噬。分子机制研究发现GA通过ATF4/CHOP途径诱导细胞自噬和凋亡，而IRE1α/XBP1s级联途径则保护HCC细胞免受GA诱导的凋亡 [41] 。α-硫辛酸可保护正常细胞免受氧化剂影响，同时诱导癌细胞的凋亡，使用α-硫辛酸处理肝癌细胞系后发现UPR相关蛋白明显上调 [42] 。Safranal可导致肝癌细胞出现S期停滞、DNA损伤、ER应激、细胞凋亡等现象 [43] 。碳离子(CI)照射可以在HCC细胞中诱导ERS，PERK通过调节ATF4的表达促进自噬并调节p53表达，后者可上调DRAM诱导自噬，并通过线粒体途径促进细胞凋亡或通过下调铁死亡关键调节蛋白SLC7A11促进铁死亡 [44] 。阿立哌唑可诱导肝癌细胞发生ERS，促进PERK和IRE1活化，导致细胞凋亡 [45] 。肝癌细胞缺乏叶酸时可导致ERS，降低迁移能力和侵袭性，并促进细胞凋亡，该效应与PERK途径有关 [46] 。

4. 总结

在本综述中，我们总结了2018年至今最新的研究结果，虽有一定的进展，但ERS与HCC的关系仍旧复杂，涉及的蛋白较多，效应各异，需要进一步探索。

文章引用

徐佳怡,吴 亮. 肝细胞癌相关内质网应激的研究进展
Research Progress of Endoplasmic Reticulum Stress in Hepatocellular Carcinoma[J]. 世界肿瘤研究, 2023, 13(02): 30-36. https://doi.org/10.12677/WJCR.2023.132005

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