中国医科大学学报  2023, Vol. 52 Issue (7): 644-648

文章信息

王煜宁, 王亚静, 张颐
WANG Yuning, WANG Yajing, ZHANG Yi
HIF-1α在肿瘤细胞糖酵解中的作用
Role of HIF-1α in glycolysis of cancer cells
中国医科大学学报, 2023, 52(7): 644-648
Journal of China Medical University, 2023, 52(7): 644-648

文章历史

收稿日期:2022-07-28
网络出版时间:2023-07-06 16:00:59
HIF-1α在肿瘤细胞糖酵解中的作用
王煜宁 , 王亚静 , 张颐     
中国医科大学附属第一医院妇科,沈阳 110001
摘要:正常细胞在有氧条件下进行氧化磷酸化,而肿瘤细胞在有氧条件下优先采用糖酵解的方式迅速供能,这一特性称为“Warburg效应”。糖酵解与肿瘤的发生、发展、侵袭及转移密切相关,是恶性肿瘤的重要特征之一。缺氧诱导因子-1α(HIF-1α)是肿瘤细胞糖酵解反应的关键调节因子,诱导细胞存活、血管生成、侵袭甚至肿瘤进展。基于HIF-1α的糖酵解通路以及相关调节因子的靶向治疗可能成为多种恶性肿瘤新的治疗手段。本文就HIF-1α在肿瘤细胞糖酵解中的作用机制及其表达与各种肿瘤的关系进行综述。
关键词缺氧诱导因子-1α    肿瘤细胞    糖酵解    
Role of HIF-1α in glycolysis of cancer cells
Department of Gynecology, The First Hospital of China Medical University, Shenyang 110001, China
Abstract: While normal cells undergo oxidative phosphorylation under aerobic conditions, tumor cells preferentially use glycolysis for rapid energy supply even under aerobic conditions—a property known as the "Warburg effect". glycolysis is closely related to tumor development, invasion, and metastasis, which is an important feature of malignant tumors. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of the glycolytic response of tumor cells, inducing cell survival, angiogenesis, invasion, and even tumor progression. Targeted therapy based on the HIF-1α glycolytic pathway and regulatory factors will probably become the latest research direction for many malignancies. In this paper, the function of HIF-1α and its effect on the glycolysis of many cancer cells is reviewed.
Keywords: hypoxia-inducible factor-1α    tumor cell    glycolysis    

缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)是肿瘤进展和靶向治疗的关键转录因子。HIF-1α的作用取决于环境中是否存在氧气。在含氧环境中,泛素蛋白酶途径会破坏HIF-1α,使其完全失活。相反,在乏氧环境中,HIF-1α逃脱破坏并进入细胞核,同时可激活HIF-1α信号通路,从而改变许多与肿瘤进展相关的因子[1]。过度表达的HIF-1α及其下游基因可通过多种方式(血管生成、细胞增殖以及诱导遗传不稳定和治疗耐药性等)加快癌症进程[2]。近年来研究[3]发现,糖代谢与癌症的发生、发展密切相关。HIF-1α作为肿瘤细胞糖代谢表型转变的重要因子,许多关键通路都是通过HIF-1α与糖酵解相关,因此,基于HIF-1α的糖酵解通路以及相关调节因子可能是肿瘤治疗的新靶点。本文就HIF-1α在肿瘤细胞糖酵解中的作用机制及其表达与各种肿瘤的关系进行综述。

1 HIF-1α在肿瘤细胞糖酵解中的作用 1.1 HIF-1α结构

HIF是一种异二聚体结合形成的转录因子,由氧敏感性的α亚单位(HIF-1α、HIF-2α、HIF-3α)和结构亚单位(HIF-1β/芳基烃受体核转运蛋白或ARNT)组成[4]。其中结构亚单位参与组成结构,不受氧含量的影响,而α亚单位与氧浓度有关,正常氧浓度下,HIF-1α由脯氨酸羟化酶羟化,并与希佩尔林道病肿瘤抑制蛋白(Von Hippel-Lindau,VHL)结合,VHL通过招募E3连接酶与HIF-1α相互作用,HIF-1α会被泛素蛋白酶体迅速降解。而缺氧情况下,HIF-1α的羟基化受到抑制,HIF-1α通过CBP/p300介导与HIF-1β形成异构体,并转移到细胞核与目标基因缺氧反应元素(hypoxia-responsive element,HRE)结合[5-6]。HIF-1α容易被细胞内氧依赖性泛素蛋白酶降解,因此HIF-1α的稳定性是调控HIF-1活性的主要决定因素[7]

1.2 HIF-1α作为转录因子参与肿瘤细胞的调控

最近研究[8]表明,几乎所有类型的肿瘤都表现出“Warburg效应”:即使在氧气存在的情况下肿瘤细胞也更可能依赖糖酵解方式来代谢葡萄糖。胶质母细胞瘤的实验研究[9]证实,HIF-1α通过直接刺激糖代谢途径中的关键酶[己糖激酶(hexokinase,HK)2和丙酮酸脱氢酶激酶(pyruvate dehydrogenase kinase,PDK)1]来增加糖酵解速度,从而提供肿瘤细胞所需的能量,使肿瘤细胞侵袭转移能力增强。乳腺癌的研究[10]证实,HIF-1α诱导乳酸盐、H+、HCO3-转运体的膜表达,乳酸含量上升使细胞内pH下降,这有助于抑制肿瘤免疫微环境。另有实验[11]证实HIF-1α对肿瘤细胞的生物学行为依赖糖代谢,HIF-1α参与肿瘤细胞高代谢状态。因此,通过抑制HIF-1α来抑制糖代谢可能是肿瘤治疗的有效措施。在缺氧和缺少营养物质环境中癌细胞重新编程细胞代谢方式,以促进其增殖和存活。肿瘤细胞基因随着氧气水平下降而发生突变。环境变化导致HIF-1α激活,通过协调代谢使肿瘤细胞能够在低氧环境中生存。除此之外,研究[12]显示HIF-1α有助于调节肿瘤细胞在缺氧情况下的增殖、凋亡、自噬、葡萄糖代谢和血管生成的多种适应性反应。

1.2.1 盐诱导活性激酶2(salt-inducible kinase 2,SIK2)对HIF-1α的调控

SIK2属于AMPK族新的丝氨酸/苏氨酸活性激酶亚家族,在代谢调控中发挥着重要作用。有研究[13]指出,SIK2促进卵巢癌细胞的脂肪酸氧化,调控脂肪组织中的胰岛素信息级联,调节脂肪细胞中的激素信息传导,表明SIK2可能在卵巢癌的代谢重编程中起关键作用。最近的研究[14]也证明,SIK2可以通过活化PI3K/AKT信号通路上调HIF-1α的表达,能够更直接地上调糖酵解关键基因的转录,从而促进糖酵解;而SIK2主要利用PI3K/AKT信号通路上调卵巢癌细胞的“Warburg效应”,调控卵巢癌细胞的葡萄糖代谢。

1.2.2 脯氨酸羟化酶(prolyl hydroxylase domain,PHD)对HIF-1α的调控

PHD属于亚铁离子和2-酮戊二酸双加氧酶超亲家族,是细胞内双加氧酶的氧传感器蛋白,广泛分布于上皮起源的正常组织,主要在细胞质中表达[15]。PHD生物活性主要依靠氧气的存在,通过直接感受氧分压的变化发挥作用。正常氧条件下,PHD2与氧分子协同作用催化HIF-1α结构域ODDD区的羟化反应,羟基化的HIF-1α与VHL融合,进而在蛋白酶体内分解。但在缺氧条件下,由于PHD依赖性氧的羟基化效果受限,即HIF-1α氧依赖的特定降解结构域无法被羟基化,VHL不能够识别HIF-1α,从而导致HIF-1α不能被分解,其表达水平迅速稳定增加,在其他关键因子介导下参与细胞低氧的适应性调控[16]

1.2.3 HIF-1α对糖酵解相关基因的调控

研究[17-18]表明,作为缺氧状态下的重要转录因子,HIF-1α也可以参与调控糖酵解受体和酶的调节基因[葡萄糖转运体(glucose transporter,GLUT)-1、HK2、PDK1和乳酸脱氢酶(lactate dehydrogenase,LDH)A],使肿瘤细胞由有氧糖酵解转化为厌氧糖酵解,从而调节肿瘤细胞的能量代谢。HIF-1α能够促进GLUT-1转录,增加糖酵解葡萄糖的摄入量[19]。通过糖酵解产生的丙酮酸盐在以HIF-1α依赖的LDHA高表达的介导下代谢为乳酸。HK2在上皮性卵巢癌中高表达且与卵巢癌化疗耐药性密切相关,HK2能使葡萄糖磷酸化为6-磷酸葡萄糖(glucose-6-phosphate,G6P),激活HIF-1α上调HK2的表达水平,从而促进糖酵解的发生[20]。研究[21]显示,在严重缺氧的条件下,HIF-1α还能诱导PDK1转录,经过三羧酸循环(tricarboxylic acid cycle,TCA)有效抑制丙酮酸脱氢酶(pyruvate de-hydrogenase,PDH)的活性,进而阻止丙酮酸转化为乙酰辅酶A。因此,HIF-1α可以通过直接刺激肿瘤细胞代谢过程中的关键因子来增加糖酵解。而轻度缺氧时,线粒体细胞色素C氧化酶活性未受损,通过将丙酮酸转化为乳酸来诱导糖酵解重编程,通过抑制HIF-1α/PDK1轴来抑制炎症,提示这可能是潜在的调节炎症过程的治疗靶点[22]

1.3 HIF-1α参与调节的信号通路

1.3.1 HIF-1α通过调节PI3K/Akt信号通路调节糖酵解

PI3K/AKT信号通路在许多肿瘤中被激活,参与调节肿瘤的增殖、生长、血管生成和转移[23]。此外,PI3K/Akt信号通路与各种酶生物效应和葡萄糖代谢密切相关[24]。PI3K/AKT信号通路通过上调诱导糖酵解刺激的酶[GLUT、HK2、血小板型磷酸果糖激酶(platelet isoform of phosphofructokinase,PFKP)、PKM2和LDH]来诱导糖酵解[25];而这些转运体以及关键酶的表达需要HIF-1α的调控。以往研究[26]表明,HIF-1α的表达受PI3K/AKT/mTOR信号通路的调控,mTOR是HIF-1α激活的上游介质,PI3K/Akt信号通路可以通过mTOR调节HIF-1α。HIF-1α激活促进血管生成和红细胞生成,导致氧气和营养物质输送增加,同时提高新陈代谢中的氧气利用率[27-28]。可见,通过PI3K/AKT/HIF-1α通路上调肿瘤细胞的有氧糖酵解,肿瘤细胞能量产生增加,从而使肿瘤细胞的侵袭能力增强。

1.3.2 HIF-1a介导AMP活化蛋白激酶(AMP-activated protein kinase,AMPK)缺失对有氧糖酵解的影响

AMPK是一种异三聚体丝氨酸/苏氨酸蛋白激酶,存在催化α-亚基、1个β-调节亚基和1个γ-调节亚基;并且AMPK各亚基在不同组织中表达。AMPK在调节细胞增殖、自噬和代谢中发挥作用[29]。AMPK作为代谢传感器,有助于维持细胞能量稳态,协调支持癌细胞的生长和增殖。当细胞能量水平下降,氧气或营养物质因血液供应不足时AMPK启动,恢复能量供应的同时可抑制肿瘤细胞的生长及分裂。相反,中断AMPK信号可促进癌细胞代谢重编程,驱动“Warburg效应”,促进肿瘤在体内的发生和进展。实验研究[30]表明,AMPKα缺失将会增强癌细胞中的“Warburg效应”,促进糖酵解并增加HIF-1α的表达。HIF-1α和AMPK信号通路是糖酵解和氧化磷酸化的主要调节剂,肿瘤细胞的代谢重新编程与二者密切相关[31]。下调HIF-1α表达、激活AMPK可以促进氧化磷酸化并抑制糖酵解,抑制肿瘤细胞增殖、转移。

2 HIF-1α表达与肿瘤的关系 2.1 HIF-1α基因、蛋白表达水平与卵巢癌的关系

HIF-1α是糖酵解的重要调节剂。HIF-1α在卵巢癌中可调节多种因子的表达,从而调控卵巢癌代谢重编程。短暂受体电位7(transient receptor potential melastatin,TRPM7)是1种独特的阳离子通道蛋白。研究[32]表明,TRPM7沉默激活AMPK并且降低HIF-1α的表达水平,增强氧化磷酸化,抑制葡萄糖摄入、糖酵解、乳酸的产生,从而抑制卵巢癌细胞的增殖,TRPM7表达上调与盆腔淋巴结转移和人卵巢癌预后不良有关。在缺氧条件下,HIF-1α上调SNHG22的表达,促进卵巢癌细胞增殖和糖酵解,引起卵巢癌患者预后不良[33]。非编码RNA-LINC00662在多种恶性肿瘤中都起到关键的作用,上调卵巢癌细胞中LINC00662,通过其与miR-375直接结合来调节细胞中HIF-1α的表达,促进糖酵解,增强卵巢癌细胞侵袭能力,导致患者预后不良[34]

2.2 HIF-1α基因、蛋白表达水平与胃癌的关系

HIF-1α表达与胃癌侵袭、肿瘤表型和预后不良显著相关[35]。其高表达与胃癌患者5年生存率、癌灶浸润深度、淋巴管/血管浸润风险以及TNM分期关系密切[36]。同时,HIF-1α表达显著增加了胃癌患者发生淋巴结转移、腹膜播散和肝转移的风险[37]。不仅如此,作为miR-138-5p的靶基因,HIF-1α影响糖酵解过程,可能参与调节低氧诱导的5-FU耐药[38]。有研究[39]表明,STAT3、SIRT3和HIF-1α蛋白均在胃癌组织中表达,通过介导STAT3表达影响SIRT3/HIF-1α调控轴,从而抑制胃癌细胞糖代谢水平。HIF-1α作为miR-186的下游靶基因,当miR-186被敲除时,糖酵解标志物,包括葡萄糖摄入量、乳酸量、ATP和NADH等均增加。miR-186通过靶向HIF-1α调节复杂的信号级联来影响葡萄糖代谢。HIF-1α激活HK2,能够增加糖酵解的能量供应,miR-186降解可部分减少糖酵解的能量供应并抑制肿瘤细胞增殖[40]

2.3 HIF-1α基因、蛋白表达水平与胰腺癌的关系

胰腺癌是最致命的恶性肿瘤之一,由于早期症状隐匿且不典型,治疗靶点有限,我国胰腺癌患者5年生存率很低,仅为7.2%[41]。胰腺癌免疫组织化学研究[42]显示,与癌旁组织相比,BZW1在肿瘤组织中过度表达。在胰腺癌细胞中,BZW1过表达能明显增加HIF-1α和c-Myc蛋白水平,过表达HIF-1α可以显著恢复敲除BZW1对胰腺癌细胞的糖酵解、存活和增殖的影响。USP25缺失会破坏HIF-1α转录活性,损害糖酵解,诱导肿瘤缺氧核心的细胞死亡。因此,USP25/HIF-1α轴是胰腺导管腺癌代谢重编程和生存的重要机制,可以用于胰腺癌的治疗[43]

2.4 HIF-1α基因、蛋白表达水平与胶质母细胞瘤的关系

中枢神经系统组织中普遍存在低氧环境,HIF-1α在胶质母细胞中高表达。有研究[44]表明,在缺氧条件下,HIF-1α在野生型Tregs细胞外酸化率显著增加。N-Myc和HIF-1α通过调节糖酵解基因促进了神经母细胞瘤的“Warburg效应” [45]。在缺氧条件下,HIF-1α降解减少而进一步稳定,随着乳酸产生增多稳定的HIF-1α与N-Myc结合使葡萄糖的摄取进一步增加[44],促进胶质母细胞瘤增殖。也有研究[46]证实,精氨酸甲基转移酶(protein arginine methyltransferases,PRMT3)可以调节多种基因的表达,在缺氧条件下可促进HIF-1α表达并增加其稳定性。因此,PRMT3的靶向药物可抑制HIF-1α表达和糖酵解,进而抑制胶质母细胞瘤细胞生长,为胶质母细胞瘤的治疗提供了新的方向。

综上所述,HIF-1α可以调控糖代谢途径中的关键酶,调节信号通路以及多种基因及蛋白质的表达水平来影响肿瘤细胞的糖酵解。肿瘤细胞中HIF-1α高表达与肿瘤的发生及不良预后相关。肿瘤细胞在微环境中不断调整自身的新陈代谢来满足能量需求,这种代谢变化是细胞内多种生长信号、癌基因以及糖酵解关键酶等多个生物学环节共同导致的。现阶段HIF-1α在肿瘤细胞糖酵解中作用的研究多为体外细胞实验,今后应对潜在的代谢途径进行全面研究,明确HIF-1α在肿瘤细胞糖酵解中的作用机制,以便使基于HIF-1α的糖酵解通路以及相关调节因子的靶向治疗成为肿瘤治疗的新方向。

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