摘要:肾细胞癌 (renal cell carcinoma,RCC) 是最常见的的泌尿系统恶性肿瘤之一。铁死亡是一种与铁依赖相 关新型细胞凋亡方式,受多种细胞代谢的调节,包括氧化还原稳态、铁吸收、线粒体活性和氨基酸、脂质和糖的代谢等。铁死亡与肾癌的发生发展密切相关,铁死亡相关基因可以导致细胞膜不饱和脂肪酸发生氧化,进而引起 细胞凋亡,一些铁死亡基因可作为肾癌早期诊断的潜在生物标志物。本文就铁死亡在肾癌中的作用机制及早期诊 断相关生物学标志物做一综述。
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高瀚 ,夏庆华.铁死亡基因在肾癌中的研究进展[J]. 泌尿外科杂志(电子版),2023,15(1):76-81. DOI:10.20020/j.CNKI.1674-7410.2023.01.14
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肾癌是泌尿系统最常见的恶性肿瘤之一[1] 。在过 去的几十年里,其发病率在世界范围内呈上升趋势, 仅 2020 年,全球范围内肾癌新确诊人数就超过了 40 万例,其中死亡人数约 20万例,占全球所有确诊 癌症人数的2.4%[2-4] 。肾癌诊断目前依赖临床症状、影 像学及病理改变,缺乏早期诊断标志物。近年来,铁 死亡基因逐渐进入大众视野,研究表明,铁死亡基因 参与肾癌的发生发展,并有早期诊断的潜力[5] 。
铁死亡是近年来发现的一种新型细胞死亡方式, 研究表明,在细胞死亡过程中通常伴有大量铁元素 积累和脂质过氧化反应[6-7] 。铁死亡的发生是铁依赖 性的,铁死亡相关诱导因子可通过不同途径直接或 间接影响谷胱甘肽过氧化物酶的生物活性,导致机 体抗氧化能力下降以及细胞中脂质活性氧 (reactive oxygen species,ROS) 的积累,最终导致细胞氧化 死亡[8-9] 。铁死亡与许多疾病的病理生理过程存在密 切关系,如肿瘤、神经系统疾病、缺血再灌注损 伤、肾损伤和血液疾病等[10-11] 。所以,探索如何通过v> 调节细胞铁死亡过程来干预相关疾病的发生发展已 成为疾病研究和治疗的热点。铁死亡在细胞形态和 功能上与坏死、凋亡、自噬存在明显不同,它不具 有典型细胞坏死的形态学特征,如细胞质和细胞器 的肿胀和细胞膜的破裂,也不具有传统细胞凋亡的 特征,如细胞收缩、染色质凝结、凋亡小体的形成 和细胞骨架的分解[12-14] 。与细胞自噬相反,铁死亡没 有形成经典的封闭双层膜结构。形态学上,铁死亡 主要表现为线粒体明显萎缩,膜密度增加,线粒体 嵴减少或消失,这是与其他细胞死亡模式不同的过程。
关于铁死亡机制研究表明,许多癌症相关基因 和信号通路可以调节铁死亡,进一步研究观察到间 充质干细胞和去分化癌细胞以及筛选的耐药癌细胞 对铁死亡诱导剂均有高度敏感[15-18] ,进一步证实了铁 死亡诱导可以作为一种新型癌症疗法的可能。由于 铁死亡是一种氧化应激诱导的脂质代谢形式的细胞 死亡,因此提出癌细胞可能具有更强烈的铁死亡倾 向似乎也是合乎逻辑的,因为肿瘤细胞具有更加活 跃的新陈代谢和更高的 ROS负荷。除此之外,已经 表明癌细胞有更高的铁元素需求量[19-20] ,这可能使他 们对铁死亡更加敏感。并且铁死亡在癌症中的作用 也取决于其特定的遗传背景。
肾透明细胞癌 (clear cell renal cell carcinoma, ccRCC) 细胞对谷氨酰胺和胱氨酸的消耗有高度敏 感性,谷氨酰胺和胱氨酸是谷胱甘肽 (glutathione, GSH) 合成所必需的成分。机体通过 GSH/谷胱甘 肽过氧化物酶 (glutathione peroxidase,GPX) 途径 来防止脂质过氧化和细胞死亡。研究证实,抑制 ccRCC 中 GSH 合成可诱导铁死亡并抑制肿瘤的生 长,这为肾癌中铁死亡的研究提供了依据。
1 胱氨酸-GSH-GPX4 轴与肾癌
2 肾癌中铁死亡相关标志物的研究
2.1 GPX4 基因与肾癌
2.2 KDM5C 基 因 与 肾 癌
2.3 MITD1 基因与肾癌
2.4 HO-1基因与肾癌
2.5 ISCA2 基因与肾癌
2.6 CSPP1 基因与肾癌
2.7 FDFT1 基因与肾癌
3 总结与展望
3 总结与展望
铁死亡是一种与铁元素含量或活性氧相关的细 胞死亡过程,参与多种生物过程,与肿瘤的发生发 展密切相关。铁死亡过程可以通过多种药物调节, 铁死亡在肾癌的发生发展中起关键作用,在肾癌中 的研究有可能筛选出新的阻断肾癌进程的靶点,通 过诱导和抑制铁死亡过程对肾癌进行早期干预,对 肾癌患者的治疗有一定的指导意义。随着研究的深 入,铁死亡在越来越多的疾病的病理生理过程中被 发现,也为治疗这些疾病提供了新的思路。此外, 铁死亡作为一种独立的细胞死亡方式,也可以与其 他类型的细胞死亡一起在疾病中发挥作用,这为联 合应用现有治疗方案提供了可能性,有助于解决某 些疾病的耐药性问题。然而,铁死亡的研究仍处于 起步阶段,许多问题仍未解决。但这并不阻碍一些 铁死亡基因有为肾癌早期诊断的生物学标志物,总 的来说,铁死亡相关基因在肾癌的研究中有广阔的 临床应用前景。
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