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Advances in Clinical Medicine
Vol. 12  No. 10 ( 2022 ), Article ID: 56875 , 6 pages
10.12677/ACM.2022.12101354

肝癌与铁死亡的研究进展

李林俞1,2，陈鑫1,2，李红玲2*

1甘肃中医药大学第一临床医学院，甘肃 兰州

2甘肃省人民医院肿瘤内科，甘肃 兰州

收稿日期：2022年9月19日；录用日期：2022年10月11日；发布日期：2022年10月19日

摘要

肝细胞肝癌(hepatocellular carcinoma, HCC)是世界范围内最常见的恶性肿瘤之一。最新的数据显示，HCC发病率排位已上升至第六位，死亡率更是高达第三位。我国是一个乙肝大国，肝硬化是乙肝患者的终末期状态，HCC更是导致肝硬化患者死亡的最主要的原因。多年来，关于索拉非尼诱导肿瘤细胞死亡模式的研究层出不穷，过去人们更倾向于认为这种模式是细胞凋亡。然而最新研究已经证实，由索拉非尼诱导肝癌细胞死亡的模式是铁死亡，而不是凋亡。这给我们探索治疗HCC开启了新的研究方向。

关键词

肝癌，席夫碱配体衍生物，铁死亡，P53

Research Advancements in Hepatocellular Carcinoma and Ferroptosis

Linyu Li1,2, Xin Chen1,2, Hongling Li2*

1The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou Gansu

2Department of Oncology, Gansu Provincial People’s Hospital, Lanzhou Gansu

Received: Sep. 19th, 2022; accepted: Oct. 11th, 2022; published: Oct. 19th, 2022

ABSTRACT

In the world, hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors. According to the most recent data, the incidence of HCC has increased to the sixth spot, while the fatality rate has reached the third spot. China has a high hepatitis B prevalence. Hepatitis B patients who have liver cirrhosis have reached the end stage of the disease, and HCC is the primary killer of people with liver cirrhosis. Numerous researches have been done over the years on the manner of sorafenib-induced tumor cell death, which was formerly more frequently referred to as apoptosis. Recent research, however, has demonstrated that ferroptosis, as opposed to apoptosis, is the mode of liver cancer cell death brought on by sorafenib. This opens a new research direction for us to explore the treatment of HCC.

Keywords:Hepatocellular Carcinoma, Schiff Base Ligand Derivative, Ferroptosis, P53

Copyright © 2022 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. 引言

铁死亡(ferroptosis)是一种新发现的、以铁依赖性的过氧化物集聚为特征的程序性细胞死亡(programmed cell death, PCD) [1] [2] [3] ，其形态学特征为细胞体积的皱缩和线粒体膜密度的增高，是一种区别于典型的细胞凋亡和其他程序性细胞死亡的新型细胞死亡模式 [4] 。在细胞内，Fe2+参与线粒体氧化磷酸化，促进脂质过氧化和活性氧簇(reactive oxygen species, ROS)的集聚，当ROS水平累积到一定程度，超过了细胞自身的抗氧化阈值，就会诱导细胞内的氧化应激过载，损害蛋白质、核酸和脂质等大分子物质，造成细胞损伤或死亡，这种模式就是铁死亡 [5] 。铁代谢异常也是铁死亡和经典的凋亡模式主要的区别之一。铁死亡不能被细胞凋亡或坏死的抑制剂所抑制，而只能被铁死亡抑制剂ferrostatin-1所抑制，说明导致铁死亡的机制并不同于细胞凋亡和坏死性凋亡 [6] 。铁螯合剂和亲脂性抗氧化剂均能抑制铁死亡。通过转铁蛋白(transferring, TRF)和转铁蛋白受体(transferrin reeeptor, TFRC)之间的相互作用，过量的铁输入可以增强铁中毒的敏感性。此外，磷脂过氧化物酶，特别是谷胱甘肽过氧化物酶4 (GPX4)和上游胱氨酸转运体SLC7A11 (也称为system Xc-)的损伤，导致细胞易受控制的脂质过氧化和铁死亡的影响。因此，游离铁积累和脂质过氧化是铁死亡的两个基本方面。

P53是一种抑癌基因，P53在肿瘤细胞周期阻滞、凋亡以及衰老等方面都发挥关键作用。近年来，许多研究发现P53参与了其它肿瘤细胞生物学行为调节从而促进肿瘤发生发展。P53依赖其特定的DNA结合序列识别结合在目的基因转录启动子上从而选择性地调节下游分子。最近Nature报道了P53通过非经典途径促进肿瘤细胞的铁死亡，他们提出P53在活性氧物质ROS累积的条件下，通过下调system XC-组分SLC7A11的表达抑制细胞对胱氨酸的摄取，导致谷胱甘肽过氧化物酶活性降低，削减细胞抗氧化能力，增强细胞对铁死亡的敏感性 [7] 。同时，研究发现，在人肿瘤细胞中SLC7A11过度表达，这种过表达能够抑制活性氧诱导的“铁死亡”，同时削弱P53介导的对肿瘤生长的抑制作用 [8] 。

2. 肝癌治疗进展

肝癌(liver cancer)是严重危害人类健康的重大疾病，其中肝细胞肝癌(hepatocellular carcinoma, HCC)占85%~90%，我国HCC发病率、患病率、死亡率均居全球前列 [9] [10] 。目前，HCC临床治疗现状仍有待提高。近年来，抗HCC治疗研究逐渐深入，开发了包括介入治疗(TACE)、纳米载药、多靶点酪氨酸激酶抑制剂TKIs、CAR-T细胞治疗等方法和药物。虽然整体疗效欠佳，但这些“靶向癌细胞生物学特性”的研究为抗HCC的研究提供了重要的参考和思路 [11] 。在HCC铁代谢干预研究中发现，以降低铁过载的生长阻滞和加剧促进铁过载的铁死亡(Ferroptosis)为策略的两种方法均显示了“铁代谢干预”在抗肿瘤中的价值，但安全性和靶向性仍未能得到很好的解决，导致“铁代谢干预”抗肿瘤的策略应用受限 [12] 。寻找低毒、高效、可控的铁谢干预的策略和方法是提高临床抗HCC治疗水平的有效途径。

3. 铁死亡与铁代谢的研究进展

铁是人体不可缺少的元素，生理性铁浓度在氧传递、电子传递、DNA合成等代谢过程中发挥多重作用 [13] 。在哺乳动物细胞中，非血红素铁和血红素铁的吸收途径涉及为后续脂质过氧化提供铁的各种转运体或受体。同时发现，病理性铁蓄积可引起细胞的氧化损伤甚至死亡 [14] 。

研究表明，铁代谢的失衡可以抑制肿瘤的生长。铁死亡是一种不同于凋亡、坏死、焦亡、自噬的全新细胞死亡方式，主要以铁稳态失衡、活性氧(reactive oxygen species, ROS)产生为主要特点。其形态学改变主要是线粒体体积缩小，双层膜密度增加，线粒体嵴减少或消失 [15] 。目前对铁死亡的研究还相对较少，其发生机制的研究主要集中于铁稳态失衡及谷胱甘肽过氧化物酶4 (GPX4)活性下降两方面 [16] 。

铁死亡通过是通过细胞内发生Fenton反应产生的 [17] ，在该反应中Fe2+离子将H2O2和脂质过氧化物转化为ROS，自身被氧化为Fe3+，而GPX4在还原型谷胱甘肽(GSH)辅助下将H2O2和脂质过氧化物分别转化为H2O和相应的醇 [18] 。铁死亡过程中ROS的主要作用是生物膜氧化损伤。膜脂富含多不饱和脂肪酸(PUFAs)，PUFAs与ROS有较高的亲和性。因此，铁代谢产生的ROS可使生物膜氧化损伤，引起细胞死亡 [19] 。

铁死亡主要是由于细胞抗氧化系统失活，尤其是依赖于system Xc-谷胱甘肽(GSH)-GPX4的抗氧化防御系统，导致脂质氢过氧化物蓄积所致 [20] 。system Xc-(谷氨酸和胱氨酸的反向转运体)反向转运体负责胞外胱氨酸的跨膜输入，并还原为胞内半胱氨酸(GSH合成的前体氨基酸)。谷胱甘肽作为谷胱甘肽过氧化酶4 (glutathione peroxidase 4, GPX4)正常功能的必要辅因子，谷胱甘肽(glutathione, GSH)是一种抗氧化酶，可淬灭磷脂氢过氧化物。硒是含硒半胱氨酸蛋白(包括但不限于GPX4)的重要组成部分，可增加铁死亡损伤时细胞的抗氧化能力。此外，亲脂性抗氧化剂(CoQ)被转化为还原型，从而以不依赖GSH的方式保护细胞免受铁死亡。system Xc-介导的胱氨酸摄取以及随后的GSH生成和GPX4激活在保护细胞免受铁死亡中发挥核心作用。

铁代谢异常也是铁死亡和经典的凋亡模式主要的区别之一 [21] 。铁死亡不能被细胞凋亡或坏死的抑制剂所抑制，而只能被铁死亡抑制剂ferrostatin-1所抑制，说明导致铁死亡的机制并不同于细胞凋亡和坏死性凋亡 [22] 。铁死亡诱导剂可分为两类：第一类诱导剂包括erastin、柳氮磺砒啶和丁硫氨酸亚砜胺等 [23] ，这一类诱导剂抑制system Xc-功能，并减少细胞内GSH的含量，以此诱发细胞氧化还原失衡；第二类诱导剂包括RSL3、DPI7、DPI10、DPI12和DPI13等一系列人工合成化合物，这类诱导剂直接抑制GPX4并且也导致过氧化物在细胞内的集聚 [24] 。最终，依赖于细胞内铁离子的异常代谢，集聚的ROS导致铁死亡的发生 [25] 。从生物化学角度来看，细胞内铁积累和PUFAs的过氧化作用是导致铁死亡的必要条件。虽然脂质过氧化诱导铁死亡的具体机制尚不清楚，但铁和脂氧合酶被认为是脂质过氧化和铁死亡的重要贡献者 [26] 。铁螯合剂(如脱铁胺和甲磺酸脱铁胺)和脂质过氧化抑制剂(如铁他汀-1和利普斯他汀-1)可以抑制铁死亡，但不能被凋亡、自噬或坏死抑制剂阻滞。 此外，血红素、血红蛋白或氯化铁处理引起的铁超载可引起细胞铁死亡 [27] 。

4. P53在铁死亡与肿瘤中的研究

GPX4、HSPβ1 (热休克蛋白β1)和Nrf2 (核因子e2相关因子2)分别通过限制ROS生成和减少细胞铁摄取来发挥铁死亡的负调控作用。相反，NADPH氧化酶和P53 (特别是乙酰化缺陷突变型P53)分别通过促进ROS生成和抑制SLC7A11 (胱氨酸/谷氨酸反向转运体的特定轻链亚基)的表达，发挥铁死亡的正向调节作用。

抑癌基因P53在肿瘤抑制中起关键作用 [28] 。虽然已经被广泛接受，P53的作用在调节细胞周期阻滞，衰老和细胞凋亡的功能有助于P53肿瘤抑制 [29] ，新的研究表明，P53也发挥其肿瘤抑制功能是通过其他许多细胞过程的监管，如新陈代谢，抗氧化防御和铁死亡 [30] 。铁死亡是一种独特的依赖铁的细胞程序性死亡形式，同时由细胞脂质过氧化所促进。研究表明，铁死亡可由P53及其信号通路以及肿瘤相关突变P53调控 [31] 。P53被报道可以通过转录抑制铁死亡相关蛋白SLC7A11的表达。同时，SLC7A11是P53的直接靶点；P53与P53结合反应元件在SLC7A11的启动子区域抑制其表达，导致增强肝癌细胞对铁死亡诱导剂的敏感性 [32] [33] 。SLC7A11常在人类不同类型的癌症，包括结肠直肠癌、肝癌和肾癌 [34] 。研究发现，在异种移植瘤模型中，异位SLC7A11的表达可抑制铁死亡，并消除P53 3KR的抑瘤功能 [35] 。同时，进一步研究结果显示了P53 4KR98，一个乙酰化缺陷P53突变体加上P53 3KR中的赖氨酸98 (K98)突变，不能抑制SLC711A的表达或诱导ferroptosis [36] 。值得注意的是，P53 4KR98导致P53失去肿瘤抑制功能；相比对于P53 3KR小鼠，P53 4KR98小鼠更易发生肿瘤发展 [37] [38] 。这些结果表明铁死亡有肿瘤抑制功能，而且P53诱导铁死亡有助于P53在肿瘤中的功能。

5. 总结与展望

目前，在癌症治疗领域，诱导铁死亡的治疗思路已趋于一致。索拉非尼现在是作为铁死亡诱导剂的金标准。此外，针对erastin和RSL3的新的药理学配方也正在出现。聚焦于铁死亡分子基础的新研究有助于破译代谢途径中单个成分之间现有的联系。最重要的是，这也可能导致新的死亡可能是发展替代治疗方法的基石。

总之，应该鼓励新的致力于基础研究的项目，以获得铁死亡诱导后细胞内相互作用的全貌。另一个有趣的领域是定义铁死亡和其他细胞死亡之间的联系，以确定它们在细胞和组织中的合作和调节。新的前沿正在打开，这将使铁死亡在未来转化医学的聚光灯下。

文章引用

李林俞,陈 鑫,李红玲. 肝癌与铁死亡的研究进展
Research Advancements in Hepatocellular Carcinoma and Ferroptosis[J]. 临床医学进展, 2022, 12(10): 9363-9368. https://doi.org/10.12677/ACM.2022.12101354

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