
根世界卫生组织[1]估计,2030年将有100多万患者死于原发性肝癌。原发性肝癌包括肝细胞癌(HCC)、肝内胆管癌和混合型肝细胞癌-胆管癌,其中HCC占比约85%[2]。HCC的发生是一个逐步的过程。慢性肝炎病毒感染、过量饮酒和非酒精性脂肪性肝炎可导致肝脏炎症和组织损伤,是HCC的主要病因。肝损伤可扰乱肝血管系统、正常血流和O2供应,形成一个缺氧的微环境。缺氧的Kupffer细胞、巨噬细胞和肝细胞可激活肝脏中的肝星状细胞,加快胶原蛋白沉积,导致纤维化和肝硬化,从而进一步加剧缺氧。缺氧也可影响不同免疫细胞(如NK细胞)的活动,并抑制HCC微环境中许多不同类型免疫细胞的浸润和积累,包括肿瘤相关巨噬细胞(TAM)、髓源性抑制细胞(MDSC)和中性粒细胞。O2水平随着HCC的发展而降低,从而促进免疫抑制微环境的形成[3]。缺氧诱导因子(HIF)是参与细胞对缺氧适应的核心参与者,并受氧感应脯氨酰羟化酶的调节。缺氧通过氧化还原效应和HIF的稳定作用影响细胞生长的诸多方面。HIF亚型可能通过改变代谢、生长和自我更新对肿瘤生长产生不同的影响,并可能高度依赖于环境。HIF通过促进血管生成影响癌细胞的迁移、侵袭和转移、增殖,促进糖酵解,治疗抵抗,免疫逃避等方式影响HCC的发病和进展[4]。探究HIF对HCC的作用机制及临床意义,有望拓展诊治HCC的新方法。
HIF是异二聚体,由α-亚基(HIF-α,包括HIF-1α,HIF-2α/EPAS1和HIF- 3α)和β-亚基(HIF-β,包括HIF-1β/ARNT1、ARNT2和ARNT3)组成。在人类和其他脊椎动物中,存在3种不同的HIF基因。在有氧(常氧)的情况下,HIF-α相互作用并与vonHippel-Lindau(VHL)蛋白结合,从而激活泛素连接酶系统,导致HIFa的蛋白酶体降解,HIF-1α蛋白的表达被抑制到非常低的水平。而在缺氧期间,脯氨酰羟化酶不活跃,导致HIF-α稳定并与HIF-1β二聚。二聚化后,HIF易位至细胞核,与包含序列5[0]-[A/G]CGTG-3[0]的启动子区域内的E-box样缺氧反应元件结合。HIF激活控制细胞氧稳态的基因,包括红细胞生成/血管生成和线粒体代谢有关的基因。缺氧细胞通过主要由HIF调控的转录和转录后机制对抗压力。这些分子变化使细胞能够适应缺氧,主要通过转用糖酵解来降低耗氧量,并减少细胞分裂(如细胞分裂)所需的能量。大多数实体瘤都有一定程度的缺氧,这与临床疗效有关。HIF活性的诱导上调了涉及癌症许多特征的基因,包括代谢重编程,细胞增殖、侵袭和转移以及对治疗的抵抗[5-6]。
除了氧依赖性机制外,HIF的表达和活性还受氧非依赖性机制的控制,这些机制调节了基因转录、mRNA翻译、蛋白质-蛋白质相互作用和HIF-1α亚基的翻译后修饰。在炎症反应中,HIF-1α基因的转录上调是以NF-κB依赖性方式实现的,并涉及信号转导和转录激活因子3(signal transducers and activators of transcription 3,STAT3)和Sp1。此外,生长因子对PI3K/ AKT通路的激活可导致HIF-1α mRNA和蛋白质合成增加。HIF-1α也通过与其他蛋白质的结合而受到调节[7]。
常氧环境中的细胞将葡萄糖转化为丙酮酸,丙酮酸进入三羧酸循环并在线粒体中氧化磷酸化,最终产生三磷酸腺苷。肿瘤细胞则表现出葡萄糖消耗增加和向糖酵解的重要代谢转变,丙酮酸转化为乳酸。即使在有氧条件下,肿瘤细胞中的这种代谢转变依然存在,被称为Warburg效应[8]。通过AKT和HIF-1α介导的MAP17表达上调,将促进Warburg效应[9]。肿瘤细胞通过在无氧糖酵解中来产生能量,相关研究发现这一过程主要由HIF-1α调节。许多参与糖酵解的关键酶是HCC细胞中直接的HIF-1α靶标,包括PGK1、PGAM1、HK2、ENO1、ALDOA、GPI、GAPDH、LDHA、PFKFB4和PKM2等[10],同时HIF-1α可诱导多种糖酵解蛋白同种型(包括GLUT1和GLUT3)的过度表达和活性增加,这对于糖酵解通量控制十分重要[11]。此外,HIF-1α增加了线粒体相关酶的表达,如丙酮酸脱氢酶激酶1,其可抑制丙酮酸转化为乙酰辅酶A,从而减少线粒体的氧化磷酸化水平和耗氧量[12]。而HIF-2α影响脂质代谢来进行能量代谢,如缺氧下,PI3K/AKT/mTOR通路可能是HIF-2α调控HCC的脂质代谢途径,进而促进HCC适应无氧环境的重要机制[13]。总的来说,研究显示HIF从不同途径促进了HCC的糖酵解,以适应低氧应激。
HIF-1α是血管内皮生长因子(VEGF)表达的主要调节因子。在缺氧条件下,高水平积累的HIF-1α上调VEGF等一系列血管生成因子的表达,增强相关mRNA的转录,最后促进肿瘤血管生成[14]。HIF-2α也是调节肝细胞中VEGF和其他血管生成因子的主要HIF[15]。HIF-2α主要作用于血管生成相关基因,包括VEGF、促红细胞生成素、VEGF受体2(VEGFR2)、血管生成素和酪氨酸蛋白激酶受体TIE-2[16]。
除VEGF外,许多其他信号分子在缺氧条件下也通过HIF依赖性机制高表达,包括胎盘生长因子、血小板衍生生长因子β和基质衍生因子1[17-19],均可促进肿瘤中的血管生成。ANG样蛋白4也被鉴定为HIF-1α的基因靶标,其可通过调节血管细胞黏附分子和整合素β1的表达来影响HCC血管生成和转移[20]。因此,HIF促瘤血管的生成可促进HCC的生长。
HIF诱导的肿瘤扩散的机制包括上皮间充质转化(epithelial-mesenchymal transition,EMT)、TWIST等基因的激活和GLUT1等参与癌症代谢的转录因子的激活。EMT涉及多种类型的肿瘤和多种肿瘤转移机制[21]。在HCC细胞中,缺氧条件下可通过SNAI1、SIP1、TGFβ、ROS、Notch、NF-κB、Wnt/β-catenin、PI3K/AKT等途径的活化来诱导EMT,上皮细胞转变为可移动的基质细胞,获得迁移到远处部位的能力[22]。细胞外基质(ECM)重塑在肿瘤侵袭和转移中发挥着至关重要的作用。参与ECM的几种酶沉积和重塑受缺氧和HIF的调节,包括基质金属蛋白酶、2-酮戊二酸5- 双加氧酶、赖氨酰氧化酶、胶原蛋白脯氨酰4-羟化酶等,同时通过HIF-1α依赖性机制,可下调HCC细胞中金属蛋白酶2组织抑制剂的表达[23]。HIF-1α/LOX通路通过依赖于肝炎反式激活蛋白X的机制,参与ECM重塑和促进HCC转移[24]。
此外,微小RNA(microRNA,miRNA)也与肿瘤的迁移和转移密切相关。例如,miR-23是一种常见的致癌基因,研究[25]显示,miR-23a/b可以通过VHL-HIF-1α通路促进HCC的发病进展。通过抑制SMC4可显著抑制HCC细胞的迁移,而HIF-1可通过转录调节和抑制miR-219来增加SMC4的表达。因此,HIF-1/miR-219/SMC4调控通路可能是促进HCC的迁移和转移一种机制[26]。此外,HIF-1α/miR-671-5p/TUFT1/AKT也可能是一种机制[27]。lncRNA也可促进HCC转移,lncRNA锌指蛋白多型2反义RNA1通过调控miR-576-3p/HIF-1α轴促进HCC的增殖和迁移[28]。此外,lncRNA可抑制HCC的转移,如lincRNA-p21可下调HIF-1α来降低VEGF水平,从而抑制HCC的侵袭能力[29]。因此,需要更多研究从非编码RNA层面来阐明HIF的作用机制,挖掘非编码RNA靶向药物。
缺氧与HIF和肿瘤细胞逃避免疫反应有关。免疫细胞的功能受HIF1依赖性信号机制的调节,在缺氧期间,HIF诱导肿瘤细胞对CD8细胞毒性T淋巴细胞和NK细胞产生抗性,其可能是HIF通过AMPK/CREB信号增加IL-10表达,分泌的IL-10通过STAT3信号通路抑制NK细胞的细胞毒性,从而促进HCC的复发和转移[30]。此外,缺氧可以上调产生腺苷的细胞外酶CD39和CD73的表达,增加其在细胞环境中的浓度。腺苷通过与其A2A受体结合,强烈抑制活化的T淋巴细胞和NK细胞的抗肿瘤功能[31]。HIF还可以通过作用于TAM来抑制对肿瘤的免疫反应。研究[32]认为,TAM通过分泌细胞因子,如IL-10、TGFβ、IL-6、VEGF和IL-8,促进肿瘤细胞的生长、侵袭和转移。
MDSC具有免疫抑制活性,可使癌症逃避免疫监视并对免疫无反应。通过MDSC介导L-精氨酸的消耗,阻碍T淋巴细胞增殖,并与T淋巴细胞受体亚基CD3的下调相关,导致T淋巴细胞受体反应降低。肝肿瘤的MDSC水平升高,MyD88-NF-κB通路的激活刺激IL-10的分泌,从而抑制树突状细胞中IL-12的表达。MDSC也通过细胞表面的TGFβ和NK受体p30诱导NK细胞失活。此外,MDSC还通过诱导CD4+CD25+叉头转录因子3+调节性T淋巴细胞的产生来抑制免疫反应从而促进了HCC的发生发展[33]。
癌症干细胞(CSC)在肿瘤的发生、发展、复发和转移中也具有重要作用。HIF因子可利用各种机制影响CSC的诱导和发育。这些机制可能是通过诱导CSC标记,CD44、ALDH,腺苷/STAT3/IL-6途径,MAPK/ERK途径,NOTCH和Wnt信号传导或其他机制促进CSC的繁殖[34]。缺氧可显著增强HCC细胞的干细胞相关特性,这种作用可以通过敲低HIF-1α或HIF-2α来消除。此外,HIF-1α特异性干扰RNA处理,在RNA和蛋白质水平显著降低CSC中CD133的表达。重要的是,EMT激活可以诱CSC特征。Notch1通过与HIF-1α的直接相互作用介导EMT诱导的CSC的过程;HIF-1α上调Notch的细胞内表达可激活EMT并诱导HCC细胞在体外获得CSC的特征。
迄今为止,大多数研究报道了HIF-1α和HIF-2α对肿瘤生长的积极作用。然而,另有研究[35]显示,HIF在一些其他癌症中表现出相反的影响,如缺氧可降低野生型(HIF-1α+/+)胚胎干细胞的增殖并增加细胞凋亡。因此,尚需更多研究探析HIF对HCC生长迁移的具体作用。
总结HIF在HCC中的作用机制见图 1。
HIF抑制剂有望成为一种有效的HCC治疗方法,抑制HIF-1α活化可能有助于阻止癌症进展,从而使生长的肿瘤细胞缺乏O2和所需的营养供应。当前已发现不同的化合物或药物可通过不同的分子机制阻断HIF的活性,包括减少HIF-1α的蛋白合成,代表药物如mTOR抑制剂、强心苷、拓扑异构酶抑制剂和合成寡核苷酸等;降低HIF-1α mRNA的水平,如前药AFP-464的氨基黄酮成分药物;增加HIF-1α的分解,如HSP90抑制剂、抗氧化剂和硒甲基硒代半胱氨酸药物;减少HIF亚基的异二聚化,如吖啶黄药物;减少DNA与HIF的结合,并降低转录活性,如蒽环类和棘霉素等[36]。研究[37-38]显示,一些中药方剂或中草药提取物也具有抑制或降低HIF-1α的作用,如益气化瘀解毒方、水飞蓟的提取物——水飞蓟素等。
HIF也可能参与了HCC化疗药物耐药性的发展。索拉非尼是一种具有抗增殖、抗血管生成和促凋亡特性的多激酶抑制剂,但由于产生耐药细胞,其疗效不佳,可能是长期索拉非尼治疗后导致补偿性生长途径的激活,或者缺氧诱导的自噬,从而使HIF介导的细胞反应触发对缺氧微环境的适应性机制。因此,HIF抑制剂可以与现有疗法联合使用,以增强常规疗法的敏感性和效果[39]。例如,辛伐他汀可通过抑制HIF-1α/PPAR-γ/PKM2轴,使HCC细胞重新对索拉非尼敏感[40]。此外,有研究[41]显示,HIF-1α可通过促进HCC干细胞特性,促进其对表阿霉素化疗药物的耐药。
然而,开展相关临床研究时必须谨慎。例如,由于HIF抑制剂可能加剧胰岛素抵抗损伤,并抑制肝再生。因此,对于因行肝脏手术的HCC患者,应停止HIF抑制剂治疗[42]。
HIF可通过多种途径影响HCC的发生发展,也因此被纳入HCC预后评估的相关研究中。有研究[43]显示,HIF-1α相关基因的过度表达与转移和病死率有关,HIF-1α阳性表达与HCC合并肝硬化患者血管浸润、TNM分期、HBV感染、肿瘤大小、门静脉肿瘤血栓显著相关。如上所述,HIF通过不同方式影响了HCC的发病和进展。因此,HIF相关指标水平的测定有望为HCC预后评估提供价值。
KIAA1199是一种与癌症转移相关的蛋白质,其与HIF-1α在许多人类癌症中上调,机制上与血管浸润、肿瘤TNM分期、HBV感染、肿瘤大小和肝硬化显著相关,提示KIAA1199联合HIF-1α检测对评估HCC患者的存活时间、预后情况有潜在价值[44]。其他如YTHDF1、DAAM2、H3K9me2、H3K9me3、Rpn10等作为HCC预后标志物也被相关研究[45-48]初步证实了临床价值,这些标志物联合HIF-1α检测或许能够作为评估HCC预后的新方法。
总结现有研究,HIF在HCC中的主要作用是通过促进糖酵解、血管生成、侵袭转移、免疫逃避、癌症干细胞等方式,影响HCC的发生发展以及对治疗耐药,也由此引出了通过HIF靶向治疗HCC和评估HCC预后的新设想。然而,HIF在HCC中的相关研究仍有诸多值得深入探究的问题:(1)既往研究主要着眼于HIF-1,HIF-2次之,而HIF-3的相关研究甚少。已有证据[49]显示,HIF3 AmRNA被差异剪接以产生多种HIF-3α变体,这些变体促进或抑制其他HIF复合物的活性,不同的HIF-3变体具有不同甚至相反的功能。(2)已有研究提供了关于HIF-2α在HCC生长和进展中的稳定性、转录活性和作用的信息,但在HCC中的确切作用尚存争议。有研究[50]认为HIF-2α在肿瘤中可能具有某些积极作用。(3)HIF检测评估预后也存在争议,且尚不完全清楚HIF-1、HIF-2、HIF-3三者在HCC中存在哪些相互作用。相关研究[51]发现,单独敲除HIF-1α或HIF-2α未能显著减小肿瘤体积(HIF-1α敲除后HIF-2α的表达增加,HIF-2α敲除后HIF-1α的表达增加),而同时敲除HIF-1α和HIF-2α之后效果可见肿瘤体积显著缩小。因此,HIF-1、HIF-2、HIF-3之间是否存在一些相互调控作用及其具体机制?如果存在相互调控作用,靶向HIF-1α治疗和HIF-1α评估预后的同时,是否要考虑HIF-2和HIF-3的影响?这些问题有待更多研究探明,以提升相关药物研发的成功率及HIF应用于临床的可靠性。
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