修回日期: 2026-03-24
接受日期: 2026-03-26
在线出版日期: 2026-03-28
缺氧诱导因子-1α(hypoxia-inducible factor-1 α, HIF-1α)是细胞适应缺氧条件的主要转录因子. HIF-1α通过调节血管生成、能量代谢、迁移、侵袭、增殖和凋亡等过程促进肝细胞癌(hepatocellular carcinoma, HCC)进展. HIF-1α是肿瘤微环境中低氧响应基因的主要调控因子, 也是实体瘤的特征性标志物. 因此,在缺氧微环境中抑制HIF-1α基因的表达可能为HCC的治疗性干预提供一种新颖的方法. 本文综述近几年HIF-1α在HCC发生、进展、转移和治疗中的作用研究进展, 为HCC的治疗提供新的认识和方案.
核心提要: 本文系统阐述缺氧诱导因子-1α(hypoxia-inducible factor-1 α, HIF-1α)转录因子通过各种通路导致肝细胞癌(hepatocellular carcinoma, HCC)发生发展、转移的近年研究进展, 介绍了HCC治疗的新见解、新策略及方法和HIF-1α在HCC治疗中的作用.
引文著录: 池肇春. 缺氧诱导因子与肝细胞癌发病机制及其在治疗中的作用研究进展. 世界华人消化杂志 2026; 34(3): 207-219
Revised: March 24, 2026
Accepted: March 26, 2026
Published online: March 28, 2026
Hypoxia-inducible factor-1 α (HIF-1α) is a major transcription factor for cells to adapt to hypoxia conditions. HIF-1α promotes the progression of hepatocellular carcinoma (HCC) by regulating processes such as angiogenesis, energy metabolism, and tumor cell migration, invasion, proliferation, and apoptosis. HIF-1α is a major regulator of hypoxia-responsive genes in the tumor microenvironment and a characteristic marker of solid tumors. Consequently, inhibition of the expression of the HIF-1α gene in a hypoxic microenvironment may offer a novel approach for therapeutic interventions in HCC. This article reviews recent research progress on the role of HIF-1α in the occurrence, progression, metastasis, and treatment of HCC, and offers new insights and potential solutions for HCC therapy.
- Citation: Chi ZC. Hypoxia-inducible factor in hepatocellular carcinoma: From pathogenesis to therapeutic potential. Shijie Huaren Xiaohua Zazhi 2026; 34(3): 207-219
- URL: https://www.wjgnet.com/1009-3079/full/v34/i3/207.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v34.i3.207
缺氧是一种以低氧水平为特征的病理状态, 在肝细胞癌(hepatocellular carcinoma, HCC)的进展中发挥重要作用. 然而, 缺氧诱导的HCC进展的确切分子机制尚未完全阐明. 缺氧在恶性肿瘤中发挥关键作用, 常因肿瘤血管组织不良以及肿瘤快速生长超出血管生成速度有关. 缺氧诱导因子-1α(hypoxia-inducible factor-1 α, HIF-1α)是肿瘤微环境中低氧响应基因的主要调控因子, 也是实体瘤的特征性标志物[1]. 据报道[2,3], HIF-1α的过表达是HCC患者预后的负性指标. 它在促进肿瘤迁移、转移、血管生成方面发挥关键作用, 并参与调节糖酵解、上皮-间质转化(epithelial-mesenchymal transition, EMT)和脂质代谢.
有氧糖酵解最初存在于HCC中, 是肝癌的一个特征, 并负责调节HCC中的增殖、免疫逃避、侵袭、转移、血管生成和耐药性. 糖溶性通路中的三种速率抑制酶, 包括己糖激酶2(hexokinase 2, HK2)、6-磷酸果糖激酶1(6-phosphofructokinase-1, PFK1)和丙酮酸激酶M2(pyruvate kinase 2, PKM2), 在HCC中有氧糖酵解的调控中起着重要作用, 并可通过多种机制进行调控, 例如磷酸腺苷激活蛋白激酶(adenosine 5'-monophosphate-activated protein kinase, AMPK)、PI3K/Akt通路、HIF-1α、c-Myc和非编码RNA. 由于有氧糖酵解在HCC进展中的重要性, 因此, 靶向其通路中的关键因素, 如HK2、PFK或PKM2的抑制作用, 是治疗HCC的潜在新疗法[4].
在HCC中, PI3K/Akt通路的激活通过外泌体和microRNA-32-5p促进血管生成和EMT[5]. PI3K/Akt通路的激活也是HCC中索拉非尼耐药和诱导多药耐药的原因. 使用PI3K抑制剂LY294002, 可以逆转HCC患者的索拉非尼耐药[6].
PI3K/Akt通过相互作用调控AMPK和HIF-1α的表达, 间接调控糖酵解酶的表达. PI3K/Akt还激活哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)的下游调控因子, 进一步激活HIF-1α, 从而促进癌细胞的有氧糖酵解、血管生成和新血管形成[7].
由于癌细胞的快速增殖和扩张, 在肿瘤组织核心存在缺氧. 1992年, Semenza等首次报道了Hep3B HCC细胞系缺氧诱导的核转录因子, 称为HIF-1α, 作为促红细胞生成响应元件, 导致参与克服缺氧效应的相关基因的转录. HIF-1α在肿瘤细胞增殖、糖代谢、血管生成、侵袭转移、多药耐药等方面发挥关键调控作用. HIF-1α在HCC患者中普遍过表达, HIF-1α的高表达与预后不良相关. HIF-1α可以控制80多个参与糖代谢、细胞存活、血管生成、侵袭和转移的基因的转录表达. 通过抑制或干扰HIF-1α的表达, 可有效抑制HCC的能量代谢和生长. HIF-1α作为HCC中糖酵解代谢的关键调控因子, 其激活也参与了瓦尔堡(Warburg)效应的调控, 主要在以下转录水平. 首先, HIF-1α作为一种转录因子, 可以促进GLUT-1的转录, 从而增强糖酵解对葡萄糖的摄取. 其次, HIF-1α可以控制几种糖酵解酶的转录, 包括HK2、PFK1、PKM2、乳酸脱氢酶(lactate dehydrogenase, LDHA)和甘油醛-3-磷酸脱氢酶(glyceraldehyde 3-phosphate dehydrogenase, GAPDH). 通过上调这些基因的表达, 糖酵解水平进一步提高. 第三, HIF-1α可促进丙酮酸脱氢酶激酶的表达, 抑制PDH活性, 导致丙酮酸转化为乳酸. 此外, 除了缺氧应激外, HIF-1α还可以通过多种信号通路, 包括PI3K/Akt/mTOR、Raf/MAPK和AMPK来调节, 导致糖酵解水平加速[4,8].
已发现非编码RNA,尤其是miRNA和lnc-RNA, 可调节Warburg效应, 主要通过调节糖基酶表达或糖分解相关通路. miR-199a-5p可通过HIF-1α进行抑制, 导致HK2表达受阻, 并导致迁移和入侵[9].
从氧化磷酸化向有氧糖酵解的代谢转变不仅是HCC的标志性特征, 还为HCC治疗提供了许多潜在的靶点. 在认识到有氧糖酵解在HCC中的重要作用后, 理解其相关的调控机制将使研究人员有机会开发新型治疗手段.
F-box only蛋白22(F盒仅蛋白22, FBXO22)已被发现可促进肝癌肿瘤的发展. FBXO22在Lys85上与40S核糖体蛋白S5(ribosomal protein S5, RPS5)相互作用并实现均匀, 从而促进其与赖氨酸泛素化位点K48相关的泛素介导在细胞质中的降解. 继RPS5的表达减少后, 发生下游PI3K/AKT信号通路的激活, 导致HIF-1α水平升高, 并导致血管内皮生长因子A(vascular endothelial growth factor A, VEGF-A)升高. 许多研究[10-12]已经证实FBXO22参与各种癌症的进展, 包括HCC, FBXO22通过RPS5/AKT/HIF-1α/VEGF-A信号轴促进HCC血管生成和转移. 值得注意的是, 抑制FBXO22可增强乐伐替尼在体外和体内的疗效. 因此, FBXO22可能成为治疗HCC治疗的潜在靶点[13].
Zhang等[14]研究发现了一种新的机制, 即FBXO22通过介导p21的泛素化和降解而在HCC的发生和发展中发挥癌基因作用. 研究还发现, 肿瘤大小和FBXO22的表达是总生存期的独立预后指标, 且临床样本中FBXO22和p21的表达呈负相关.
HCC的一个特征是代谢重编程[15,16], 肝癌细胞将其能量产生从氧化磷酸化转变为有氧糖酵解, 这种现象被称为Warburg effect, 是肿瘤细胞的一个特征, 即使在富氧的微环境中, 其葡萄糖吸收率和乳酸分泌率也有所增加[17]. 这种现象以增加有氧糖解为特征, 使癌细胞能够获得更多能量和中间代谢物, 以促进不同生物过程的生物合成. 有累积的研究表明[18], 线粒体功能障碍是癌细胞中增强有氧糖酵解的重要原因. 肿瘤因子(如c-Myc和HIF-1α)的异常激活, 以及肿瘤抑制因子(包括p53)的失活, 有助于重新编程的葡萄糖代谢和线粒体功能障碍[19,20]. 此外, 包括HK2、PKM2和LDHA在内的关键代谢基因的表达和活性升高已被记录在多种人类癌症中, 且与较差的患者生存结果相关[21].
这种代谢转变通过提供必要的生物合成前体来支持肿瘤细胞的快速增殖[22]. 这种代谢转换不仅为肿瘤生长提供能量, 还促进了免疫逃逸、血管生成和转移的肿瘤微环境(tumor microenvironment, TME)的形成[23,24]. 因此, 靶向关键代谢通路已成为癌症治疗中的一种有前景的方法.
AMPK-HIF-1α轴在调控癌症代谢中发挥核心作用, 尤其是在代谢应激条件下[25]. AMPK的激活通过下调HIF-1α以及糖酵解相关调节因子HK2、PKM等, 促进氧化磷酸化等分解代谢过程, 同时抑制糖酵解等合成代谢过程[26].
新近研究表明[27], 代谢重编程还会对肿瘤微环境产生深远影响, 尤其是在血管生成和免疫细胞功能方面. 乳酸是糖酵解的关键副产物, 它通过刺激血管内皮生长因子(vascular endothelial growth factor, VEGF)的产生并促进血管内皮细胞增殖来促进血管生成[28]. 除了血管生成外, 乳酸在调节免疫细胞功能方面也至关重要, 特别是在肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)的极化过程中[29]. 肿瘤细胞常常将巨噬细胞从促炎、抗肿瘤的M1表型驱动至抗炎、促肿瘤的M2表型[30]. 乳酸介导了这种转化, 从而形成一种免疫抑制性微环境, 使肿瘤能够逃避免疫监视[31].
程序性死亡配体-1(programmed death ligand-1, PD-L1)是一种免疫检查点蛋白, 在癌细胞中经常上调以抑制细胞毒性T淋巴细胞(cytotoxic T lymphocytes, CTL)的活性并逃避免疫监视[32]. 最近的研究表明[33], 代谢途径, 包括由AMPK调控的代谢途径, 可以影响PD-L1的表达. 莲心碱(Liensinine)显著降低了HCC细胞中PD-L1的转录和蛋白水平, 这可能有助于增强免疫反应. 研究揭示PD-L1表达的降低被证明是由AMPK激活介导的, 进一步将Liensinine的代谢重编程效应与其免疫调节活性联系起来. 这表明Liensinine不仅靶向肿瘤代谢, 而且还作为免疫检查点调节剂, 使其成为免疫治疗的有希望的辅助药物, 通过AMPK和HIF-1α调控作用, 影响代谢重编程和血管生成; 通过激活AMPK介导的内质网应激调节HIF-1α的泛素化[34] .
亮氨酸-酪氨酸-精氨酸基序2(leucine-tyrosine-arginine motif 2, LYRM2)与HIF-1α相互作用, 增强了HIF-1α的蛋白质稳定性, 进而促进细胞糖解并抑制线粒体呼吸. 此外, 由LYRM2介导的葡萄糖代谢重编程与其在促进HCC生长和转移方面所起的作用有关. 研究指出[35], LYRM2是HCC中一种新型致癌蛋白, 并通过增强HIF-1α依赖性葡萄糖代谢重编程, 阐明了其对HCC进展的贡献.
HIF-1α、p53和c-Myc是葡萄糖代谢的关键调节因子, 影响参与细胞糖酵解和线粒体氧化磷酸化的基因[36]. LYRM2过表达导致HIF-1α蛋白水平升高, 而不影响P53和c-Myc水平. 作为Warburg效应的关键调节因子, HIF-1α促进糖酵解调节基因的转录, 将细胞糖代谢从氧化磷酸化转变为有氧糖酵解, 并抑制线粒体呼吸[37]. HIF-1α的下调阻断了LYRM2对Warburg效应的促进作用, 表现为糖酵解减少和线粒体呼吸增强. 这些发现表明LYRM2通过提高HIF-1α的蛋白水平来调节代谢重编程. 在HCC患者中, HIF-1α水平升高与预后不良相关, 并导致索拉非尼耐药[35]. 然而, 关于HIF-1α与LYRM2之间的调控关系, 以及LYMR2/HIF-1α轴的治疗潜力, 仍有几个问题尚未解决, 未来需要进一步验证. 此外, LYRM2通过增强HIF-1α的蛋白质稳定性来促进葡萄糖重编程. 这表明LYRM2可以作为HCC的生物标志物和治疗靶点.
最后Fan等[35]研究指出LYRM2与HIF-1α相互作用, 增加HIF-1α蛋白的稳定性, 导致HCC细胞中HIF-1α蛋白水平升高. 激活的LYRM2/HIF-1α轴增加关键糖酵解酶(HK2、LDHA、PKM2)和糖转运蛋白1(glucose transporte, GLUT1)的表达, 激活细胞糖酵解, 导致HCC的生长和转移.
对氧磷酶-1(paraoxonase-1, PON1)在肝脏中特异性表达, 并对多种肝脏疾病具有重要作用. PON1是一种代谢调节剂, 可抑制调节性T(Treg)细胞介导的免疫抑制, 从而抑制HCC进展. 从机械学上讲, PON1可促进冯·希佩尔-林道(Von Hippel-Lindau, VHL)肿瘤抑制基因介导的缺氧诱导HIF-1α的降解, 从而促进黄斑酸盐的生成, 并限制干细胞在HCC微环境中的积累. 在临床环境中, 较高的PON1表达与HCC患者预后改善相关. 重组PON1蛋白有效阻碍了肿瘤生长. 此外, 通过槲皮素增强Pon1表达, 使HCC在小鼠HCC中的抗程序性死亡-1(programmed death 1, PD-1)治疗效果增强[38].
在HCC的小鼠模型中, 肿瘤细胞中PON1基因的过度表达会以依赖Treg细胞的方式抑制肿瘤的生长. PON1通过Von Hippel-Lindau蛋白(pVHL)介导的HIF-1α的泛素化作用, 减少了肿瘤微环境中的乳酸生成, 从而降低了Treg细胞在肝癌组织中的浸润程度. 此外, 槲皮素能够上调PON1的表达水平, 这使得肝癌小鼠对PD-1疗法更加敏感[38]. 综上所述, PON1作为一种代谢调节因子, 可以通过缓解Treg细胞所引发的免疫抑制作用来抑制肝癌的发展. 因此, 增强PON1的表达可能是一种具有前景的肝癌辅助免疫治疗策略. 越来越多的证据表明, 异常的代谢重编程(癌症的一个标志)是形成免疫抑制微环境的罪魁祸首[39]. 乳酸调节TAM信号传导和基因表达, 直接促进肿瘤的发展[40]. 同时, 肿瘤细胞来源的琥珀酸盐可以激活琥珀酸受体SUCNR1, 从而引发促肿瘤的TAM极化[41]. 此外, 三酰基甘油生物发生被证明可以促进TAMs的免疫抑制功能[42].
血清PON1是微血管侵袭的一个强有力的生物标志物[43], 但PON1集中化在HCC发生中的功能作用仍不清楚. 利用免疫系统对抗HCC已被确定为一种有效的治疗策略[44,45]. 然而, 免疫疗法的效果受到TME免疫抑制特性的限制[46,47].
近年来, 肿瘤免疫治疗已成为癌症治疗中最成功的策略之一, 尤其是晚期HCC. 肿瘤血管生成是肿瘤生长和增殖的关键因素, 在肝癌的免疫调节中起着举足轻重的作用. HCC中观察到的高度血管生成导致血管结构和功能异常, 不仅促进肿瘤生长, 还会引起TME内缺氧和酸中毒, 从而通过多种机制抑制免疫应答. 鉴于肿瘤血管在免疫系统中的调节作用, 将抗血管生成治疗整合到当前的免疫治疗方法中提供了一种新的治疗选择[48].
血管生成级联是一个多步骤的过程, 由毛细血管启动, 并受到不同类型的特化内皮细胞和血管周围细胞的影响. 这些血管生成途径参与肿瘤的进展、侵袭、转移和耐药性. 在缺氧的情况下, HIF-1α和VEGF诱导的尖端细胞中的Delta-样蛋白4(delta-like protein 4, Dll4)信号和尖端细胞中的Notch信号(Dll4-Notch通路)促进新生的血管生成的发生[49,50]. 血管内套叠发生时, 现有的血管分裂并分成两支血管, 这是一个过程, 通过血管壁内陷开始于腔内柱; 这些柱可以在基底膜完好的情况下穿过血管管腔, 导致血管分裂. VIis在血管网络的稳定区域被激活, 并受到缺氧、血流动力学变化和剪切应力的影响[51], 参与这一过程的分子包括MMT1-MMP、EphrinB2/EphB4-MAPK/ERK、Notch-EphrinB2/EphB416和SDF-1/CXCR4. 然而, 抗血管生成治疗后可刺激Ⅵ, 并可能导致对治疗的抵抗[52].
血管拟态(vascular mimicry, VM)是另一种机制, 通过这种机制, 癌细胞将自己重新定位到独立于内皮细胞的结构化血管通道中, 这有助于癌症的进展和侵袭性[53]. 缺氧血管生成级联在VM中是至关重要的[54], 因为激活的HIF-1α/VEGFA信号通路促进HCC中的VM[54]. 此外, HIF-1还调节其他上皮转化相关分子的表达, 包括扭曲、液态氧和基质金属蛋白酶, 以及HCC中的Snail/FBP1/VEGF通路, 促进细胞外基质重塑和VM[55]. Nrf2/ASPM轴在缺氧条件下驱动HCC中的VM, 为HCC提供了潜在的治疗靶点[56].
TME是一个复杂的细胞生态系统, 以缺氧、免疫逃避和血管生成为特征, 是肿瘤细胞、成纤维细胞、浸润性和常驻免疫细胞、细胞因子、细胞外基质和脉管系统相互作用的地方. TME是由肿瘤细胞组织的, 由于它与VEGF活性增加和T细胞功能障碍相关, TME代表了一个安全的生态位来抵消免疫系统的激活[57], 包括CTL的衰减和Tregs的扩增. 大多数癌细胞在这种慢性免疫抑制的坏死炎症环境中进化, 这有利于HCC的进展. 重要的是, 肿瘤血管的形成支持免疫重塑. 血管生成相关基因调节HCC患者TME的多样性和复杂性, 预测侵袭并指导免疫治疗的选择[58]. 并发现肿瘤血管与免疫抑制微环境相关[59]. 血管网络的破坏和间质压力过高是CTLs及治疗性药物迁移的物理屏障. 肿瘤血管还可通过缺氧抑制免疫细胞活性[60], 而Tregs和2型传统树突状细胞(type 2 conventional dendritic cells, cDC2s)则通过缺氧信号驱动免疫抑制[61]. 在缺氧条件下, 血管生成因子的过度表达会驱动异常血管生成, 从而促进免疫细胞滞留, 并营造有利于肿瘤发展的免疫抑制微环境[48]. VEGF通过多种信号通路抑制免疫监视, 诱导M2型TAMs产生, 损害树突状细胞(dendritic cell, DC)的成熟, 促进Tregs扩增, 并触发CD8+ T细胞凋亡[62].
缺氧也明显具有免疫抑制作用, 因为它会降低T细胞的功能, 并通过线粒体重编程, 驱动T细胞衰竭[63]. 缺氧会改变T细胞对其他信号的反应, 从而增加免疫抑制因子如PD-L1 22、CCL 20/IDO、IL-6、IL-10、TIM-3和CTLA-4的水平. 低氧条件下T细胞IL-2、TNF和IFN-γ的分泌受损; 然而, CTLA-4的表达上调, 增加了肿瘤浸润淋巴细胞对负调控的敏感性[64]. 缺氧诱导HCC中ENTPD2的表达, 导致细胞外5′-AMP升高, 从而促进髓源性抑制细胞(myeloid derived suppressor cells, MDSCs)的维持. CCL-22和CCL-28通过ERK/NF-κB/CC20/CCR6途径通过TREM-1+TAM)吸引CCR6+Foxp3Treg进入肿瘤[65]. 并通过TREM-1+TAMs通过ERK/NF-κB/CC20/CCR6通路吸引CCR6+Foxp3+Tregs. Tregs的存在导致cDC2s上抗原呈递HLA-DR的丢失, 这会调节免疫反应和血管生成, 并导致有效的免疫逃逸. 此外, 研究发现[66]免疫抑制性髓系亚群(如M2巨噬细胞和cDC2s)在高缺氧肿瘤区域中显著富集.
缺氧下游的血管生成因子通过直接抑制抗原呈递细胞以及通过增强Tregs、MDSCs和TAM的作用来驱动免疫抑制[67]. VEGF可降低肿瘤血管内皮细胞中ICAM-1和血管粘附分子的表达, 从而阻止免疫细胞的浸润[68]. VEGF刺激Tregs的增殖, 阻断VEGF-A/血管内皮生长因子受体(vascular endothelial growth factor receptor, VEGFR)转导信号可抵消肿瘤细胞对Tregs的诱导. VEGF抑制来自前体的DC的成熟, 使肿瘤细胞能够逃避免疫监视[69], 并诱导MDSCS的扩增[70]. VEGF显著增加巨噬细胞上M2标志物的表达. 在一项研究中[71], 在VEGF耗尽的环境中培养的TAMs表现出较低水平的与肿瘤进展相关的分泌细胞因子, 并且诱导免疫耐受的能力下降. VEGF还会导致CD8+CTLs的耗竭, 阻断VEGF可协同调节肿瘤中CD8+ T细胞的免疫活性, 增强其产生细胞因子的能力[72].
lncRNAs在HCC进展和血管生成中的作用仍有待深入了解. 此种lncRNA又称为HCC进展和血管生成相关RNA(progression and angiogenesis associated RNA in HCC, PAARH), 功能获得和功能缺失实验表明, PAARH可促进HCC细胞的增殖、迁移和侵袭, 抑制HCC细胞凋亡, 并在体内促进HCC生长和血管生成. 此外, 研究发现[73]PAARH可与HIF-1α亚基物理结合, 促进HIF-1α募集至VEGF启动子区域, 并在缺氧条件下激活VEGF的表达, 这解释了促进血管生成的作用机制.
在HCC中, lncRNA16 GPC3-AS1促进细胞增殖和迁移[74]. lncRNA ANCR促进HCC转移[75]. lncRNA的分子机制也复杂多样[76]. 胞质lncRNA的重要机制之一是结合微小RNA(miRNAs)[77]. miRNAs是另一类具有约19-25个核苷酸长度的调控非编码RNA, 众所周知它们会抑制其靶基因的表达[78]. lncRNA可解除miRNAs对其靶基因的抑制作用. 这些lncRNA也被归类为竞争性内源RNA. lncRNA的另一种作用机制是与蛋白质物理结合, 并调节所结合蛋白质的表达和/或功能. 例如, GPC3-AS1物理结合PCAF, 将PCAF招募至磷脂酰肌醇蛋白聚糖-3(glypican-3, GPC3)基因, 从而激活GPC3的表达[74]. MRCCAT1物理结合PRC2, 将PRC2招募至NPR3, 从而抑制NPR3的转录[79]. 然而, lncRNA对HCC TME, 特别是血管生成的潜在贡献仍有待阐明. 目前研究结果表明[73], lncRNA不仅增强了HCC细胞的恶性表型, 还促进了血管生成.
circPRDM4是HCC中与缺氧相关的环状RNA. 缺氧是肿瘤的共同特征[80]. 细胞对缺氧的反应涉及肿瘤进展的几个关键方面, 特别是抗癌免疫. 缺氧影响肿瘤免疫, 并在调节抗PD-1/PD-L1治疗癌症的疗效中起关键作用. 缺氧导致HIF-1α依赖性PD-L1上调, 抑制T细胞活化. 因此, 研究缺氧条件下的抗肿瘤免疫可能有助于开发新的HCC免疫治疗策略[81].
环状RNAs(circRNAs)是一种共价闭合环状结构, 没有5'或3'端, 且对RNA外切酶具有抗性, 这使其具备作为潜在生物标志物和治疗靶点的有利特征[82]. circRNAs在多种生物学过程中发挥基本调控功能已被证实[83]. circRNAs的失调在PD-1/PD-L1介导的抗肿瘤免疫中起着至关重要的作用. circIGF2BP3/PKP3轴通过促进PD-L1的去泛素化促进肝癌细胞的免疫逃逸. Chen等[81]在HCC研究显示circPRDM4将HIF-1α招募到CD274的启动子上, 并增强HIF-1α介导的CD274启动子转录激活. 随后, circPRDM4增加了肿瘤中PD-L1的表达水平, 抑制CD8+ T细胞浸润, 并促进HCC中的免疫逃逸.
circBART2.2通过结合RIG-I促进PD-L1的转录, 在GC中导致随后的免疫逃逸. circDLG1与miR-141-3p相互作用, 增加CXCL12的表达, 从而促进胃癌对基于抗PD-1的治疗产生耐药性[84]. HIF-1α是缺氧条件下的核心调节因子, 已被证明是PD-L1的直接调节因子. 据报道[85], SLC7A11通过HIF-1α级联上调PD-L1表达, 并有助于形成免疫抑制微环境, 从而促进HCC转移.
circPRDM4在缺氧引起的免疫抑制微环境中所起的作用, 不仅为理解肿瘤细胞的免疫逃逸机制提供了新的见解, 还为癌症免疫治疗提供了新的预后生物标志物及治疗候选靶点.
胞质多聚腺苷酸化元件结合蛋白(cytoplasmic polyadenylation element-binding protein, CPEB)家族(CPEB1-4)对于转录后基因表达调控至关重要. 这些蛋白质具有共同的C端RNA结合结构域, 负责结合靶mRNA 3'非翻译区内的特定胞质多聚腺苷酸化元件, 从而促进翻译. CPEB家族在维持体细胞组织的细胞内稳态中发挥重要作用, 并调节多种过程, 如突触可塑性、细胞增殖、极性和衰老. CPEB2属于CPEB蛋白家族, 介导靶mRNA的胞质多聚腺苷酸化并调节其翻译效率[86]. EMT通过调节细胞-细胞接触、细胞-细胞外基质相互作用, 并协调上皮细胞向间质表型的转化, 在驱动肿瘤细胞转移中起关键作用[87]. 复杂的EMT调控网络涉及lncRNA、miRNAs、转录因子及其他信号分子的相互作. 越来越多的证据表明, miRNAs, 特别是miR-210-3p, 在HCC的发生、发展和转移中发挥重要作用. miR-210-3p作为一种原癌基因, 是一种缺氧响应性miRNA, 在多种癌症中促进血管生成、转移和肿瘤生长[88]. 此外, HIF-1α作为一种转录因子, 已被证实与介导对缺氧的适应性反应以及在HCC中调控EMT和转移有关[89].
CPEB2通过miR-210-3p通路抑制EMT表型在降低HCC转移中的关键作用. 缺氧以及HIF-1α/miR-210-3p/CPEB2调控环路的参与, 为HCC进展的分子机制增添了另一层复杂性. 在HCC组织中, CPEB2的表达下调且与miR-210-3p的拮抗作用相关. 此外, CPEB2在肝癌细胞系和组织中均呈低表达, 且低CPEB2表达与转移和EMT过程相关. 研究结果表明[90], CPEB2可能成为HCC未来诊断标志物和精准医学治疗靶点.
钾通道聚化结构域包含1(potassium channel tetramerization domain-containing 1, KCTD1)基因已被鉴定为一种转录抑制因子, 并与激活蛋白2(activator protein-2, AP-2)转录因子家族相互作用, 抑制AP-2转录活性. KCTD1的生理意义已经被阐明, KCTD1通过与AP-2α(一种已知的脂肪形成抑制剂)的相互作用促进脂肪形成[91]. KCTD1在人类HCC组织中的表达上调. KCTD1的促肿瘤作用是通过增强HIF-1α/VEGF信号通路发挥的, 这一作用被靶向KCTD1 3'UTR的肿瘤抑制基因miR-129-5p逆转. KCTD1下调使HCC细胞对索拉非尼敏感, 联合治疗可通过基于外泌体的递送抑制HCC的发展[92].
在目前的研究中, KCTD1的表达水平在HCC组织中是可变的, 但在47%的HCC样本中检测到KCTD1的高表达, 并且KCTD1的表达与肿瘤分级呈正相关. 据报道[93,94], miR-129-5p和miR-16-5p在各种恶性肿瘤的发生和发展中起作用, 并阻断HCC的进展[95]. 作为Myc的阴性靶点, miR-129-5p可以通过靶向线粒体基质蛋白丙酮酸脱氢酶激酶4来阻断糖酵解, 抑制HCC. HIF-1α与芳香烃受体核转位因子(aryl hydrocarbon receptor nuclear translocator, ARNT)异二聚, 通过与VEGF启动子中的缺氧反应元件结合, 促进VEGF的表达. 一些因子如特异性激活因子1和HIF-1α被发现可以调节VEGF的表达. KCTD1可以增强HIF-1α/ARNT异源二聚体的稳定性, 从而激活下游VEGF/p-VEGFR2/p-AKT/HIF-1α信号级联的表达, 形成正反馈回路. 在机制上, KCTD1与HIF-1α相互作用增强HIF-1α的稳定性, 同时降低鬼笔(毒)环肽(phalloidin, PHD)2/3和pVHL肿瘤抑制基因的表达, 而KCTD1的敲低促进HIF-1α的降解以结合活化的PHD2/3和pVHL, 这表明KCTD1和pVHL蛋白在结合HIF-1α方面存在潜在的竞争. 并且KCTD1与转录因子AP-2相互作用, 通过JASPAR数据库分析VHL肿瘤抑制基因和PHD2/3基因的启动子中存在典型的AP-2结合位点, 提示KCTD1可能通过其他复合物间接影响HIF-1α的表达[92].
索拉非尼(sorafenib)可抑制RAS/RAF/MEK/ERK通路, 并阻断人HCC中的肿瘤增生和血管生成. 索拉非尼显著增强KCTD1敲低诱导的HCC细胞凋亡, 这种协同作用在肝内HCC小鼠模型中得到证实, 表明KCTD1敲低可增加HCC细胞对索拉非尼的敏感性. 外泌体参与非HCC细胞与HCC细胞之间的相互作用, 并调节HCC的进展[96]. 外泌体可转移miRNA, 从而为包括HCC在内的多种肿瘤提供治疗益处[97]. 过表达miR-129-5p的外泌体显著抑制肝内肿瘤的生长, 且miR-129-5p与索拉非尼联合使用可显著抑制HCC的进展. 这些发现提示, 联合使用索拉非尼和KCTD1敲低可能是一种治疗晚期HCC的新策略[98].
细胞周期抑制剂通过干扰素基因刺激因子(stimulator of interferon genes, STING)信号通路部分发挥抗癌作用. Wong等[99]研究证实, 紫杉醇(微管稳定剂)、帕博西尼(细胞周期蛋白依赖性激酶4/6抑制剂)以及AZD1152和GSK1070916(Aurora激酶B抑制剂)除了阻滞细胞周期外, 还具有其他抗癌功能. 它们持续导致细胞质DNA积累和DNA损伤, 这意外地触发了细胞质DNA传感器死亡盒解旋酶41(DEAD-box helicase 41, DDX41), 并激活STING以分泌促炎性衰老相关分泌表型因子(senile associated secretory phencotype factors, SASPs). DDX41是HIF的转录靶标. 缺氧通过HIF-1诱导DDX41的表达, 使缺氧的HCC细胞对STING激活和与SASP产生的抗有丝分裂药物更为敏感. SASPs触发肿瘤中免疫细胞浸润以清除癌细胞. 使用细胞周期抑制剂, 特别是紫杉醇与抗PD-1联合使用时, 通过扰乱小鼠HCC生长延长了生存期.
增强现有细胞周期抑制剂在HCC治疗中的疗效. 细胞周期抑制剂是对HCC外具有强效化疗作用的药物. 目前市场上有许多针对细胞周期不同阶段的细胞周期抑制剂. HCC可能对这些抑制剂产生耐药性, 且一些临床试验表明, 单药治疗在HCC中效果不佳[100].
缺氧对癌症发展的影响. 氧气消耗在肿瘤中至关重要, 它通过持续产生ATP提供充足的能量以支持快速增殖, 因此肿瘤倾向于在血管附近生长. 然而, 肿瘤可能生长过快, 以至于超出血液和氧气的供应, 从而导致慢性缺氧. 肝脏中的氧气水平从肝动脉周围区域逐渐降低, 再到门静脉周围区域, 进一步降低至静脉周围[101]. 当肿瘤组织中的平均氧分压下降时, 代谢功能会受到损害. 一方面, 缺氧可能通过破坏DNA修复、增加p53来引发细胞周期停滞、凋亡或坏死, 从而延缓生长并诱导细胞死亡; 另一方面, 它可能通过HIF促进细胞对压力的适应, 例如诱导糖酵解、血管生成和无氧代谢, 并通过帮助细胞脱离、EMT和黏附来促进肿瘤细胞迁移和转移, 从而促进生长和存活[102]. 尽管缺氧可以促进炎症并导致免疫细胞浸润, 但它更有利于招募具有促肿瘤免疫亚群的免疫细胞, 而非抗肿瘤免疫亚群, 从而导致肿瘤逃避免疫监视和肿瘤侵袭性增强[103,104]. 此外, 缺氧被认为与对化疗和放疗的耐药性有关, 缺氧可被视为一把双刃剑: 它可能诱导细胞死亡并抑制肿瘤生长, 但相反也可能促进血管生成并支持肿瘤生长. DDX41是一种受HIF调控的基因, 在缺氧条件下其表达会上调. 由于DDX41的上调与较差的生存率相关, 而缺氧与化疗和放疗抵抗以及不良治疗结果相关, 因此缺氧和DDX41均被认为对HCC患者不利. 联合细胞周期抑制剂与阿替利珠单抗和贝伐珠单抗的潜在价值. 免疫检查点抑制剂阿替利珠单抗与抗VEGF抗体贝伐珠单抗的联合疗法目前已是HCC最有效的一线治疗方案[105]. 美国食品药品监督管理局(Food and Drug Administration, FDA)批准的一线疗法包括酪氨酸激酶抑制剂索拉非尼和乐伐替尼, 仅能使晚期HCC患者总生存期(overall survival, OS)延长3 mo, 而二线疗法可将经索拉非尼治疗后肿瘤进展患者的OS提高至1.6-2.8 mo[106]. 然而, 抗血管生成疗法(如抗VEGF)会限制血管发育, 从而引发肿瘤内缺氧, 而缺氧环境有利于肿瘤生长[107]. 因此, 未来有可能将细胞周期抑制剂与阿替利珠单抗和贝伐珠单抗联合使用, 以在HCC中实现最有效的抗肿瘤反应.
细胞周期抑制剂的作用远不止其经典的内在细胞周期效应, 还包括基因组不稳定性、活性氧产生、DNA损伤、胞质积累、衰老和凋亡等. 它们还通过DDX41/STING/TBK1/IRF3/7通路触发SASPs的表达, 从而显著促进先天性和适应性细胞毒性免疫细胞向肿瘤核心募集, 以进行癌症监测和清除. 细胞周期抑制剂与免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)的联合治疗尤其是在不良的低氧环境中对HCC显示出增强的疗效[99].
乐伐替尼(lenvatinib)是一种用于HCC一线治疗的靶向药物. 迫切需要更深入地了解HCC对lenvatinib的耐药机制. HIF-1α途径激活驱动的癌症干细胞增加是HCC获得性lenvatinib耐药的原因. 非肌肉肌球蛋白重链9(MYH9)Ser1943位点磷酸化, p-MYH9(丝氨酸3-羟基丙氨酸1943, Ser1943)可以募集泛素特异性蛋白酶22(ubiquitin-specific protease 22, USP22)去泛素化并稳定lenvatinib耐药HCC中的HIF-1α. 临床上, p-MYH9(Ser1943)在HCC样本中表达上调, 预示预后不良和LR[108].
Lenvatinib是一种多靶点酪氨酸激酶抑制剂, 可抑制VEGFR1-3、FGFR1-4、PDGFR-α、KIT和RET. Lenvatinib在总生存期中表现出与索拉非尼的非劣效性, 但表现出更高的无进展生存期, 为HCC患者提供了另一种有希望的选择. 它已成为继索拉非尼之后第二个被批准用于晚期HCC的一线药物[109].
癌症干细胞(cancer stem cells, CSCs)具有肿瘤生成、自我更新、转移和化疗的抗药性, 被广泛认为是导致HCC进展的驱动因素[110]. 据报道[111,112], 激活Notch、Wnt/β-catenin和Hippo信号通路有助于HCC干细胞的发生, 靶向这些通路可能恢复耐药. 在研究HCC中, 了解驱动CSCs的分子机制至关重要, 以便建立靶向治疗机制, 有效消除这些侵袭性癌细胞并增强患者的治疗效果. HIF-1α和HIF-1β形成对氧敏感的转录因子HIF-1, 这是一种主要的转录因子, 可促进多种肿瘤的进展. HIF-1α通过调控靶基因的转录, 参与CSCs的发生[113]. 缺氧下, 氧量降低可导致HIF-1α的稳定. HIF-1α利用HIF-1β进行二聚化, 并转入细胞核内以与缺氧反应元件结合. HIF-1α诱导转录因子OCT4和SOX2与PROM1促进剂结合并增加干细胞的聚集性. HIF-1α直接靶向Hippo通路效应剂三唑衍生物并调节CSCs. HIF-1α介导的是HIF-1α在CSCs中的NOTch和Wnt/β-catenin通路[114]. 此外, HIF-1α驱动GLUT1、HK2和LDHA(肿瘤糖解的关键酶)的转录[115]. 粘蛋白-1(MUC1)可防止HIF-1α降解, 并增强EGLN2和NF-κB在重要作用之间的化学敏感性[116]. 缺氧状态会减弱EGLN2对NF-κB信号通路的抑制作用, 从而促使HIF-1α与MUC1-C形成循环反馈, 进而增强HCC的化学抗性.
MYH9是非肌肉肌球蛋白Ⅱ(myosin Ⅱ)的一个亚基, 作为一种与骨架相关的蛋白质发挥作用. 在癌症中, MYH9通过多种功能参与癌症发展, 例如作为转录因子和去泛素化酶[117]. 因此, MYH9参与HCC干性和耐药的机制具有重要意义. 近期研究集中在MYH9磷酸化在癌症进展中的作用.
口服人蛋白激酶CK2抑制剂Silmitasertib(CX-4945)已被FDA批准作为孤儿药用于胆管癌(CCA)的治疗. CX-4945的应用有效抑制了CCA的发展, 抑制了HIF-1α的表达[118]. 这些发现突出了CX-4945作为临床HCC患者的新型治疗剂的潜力.
总之, 研究阐明了MYH9和p-MYH9(Ser1943)/USP22/HIF-1α轴在肝癌中促进癌变和耐药的机制. 分别靶向p-MYH9(Ser1943)和USP22, CX-4945和S02, 可以消除HIF-1-1α-诱导的耐药, 为HCC和耐药患者提供潜在有效的治疗选择.
鸦胆子素A(Ailanthone, AIL)是中药臭椿(Ailanthus altissima)树皮的主要活性成分, 已被证明具有抗肿瘤、抗疟疾、抗炎症、抗过敏和抗微生物等特性[119,120]. AIL通过PI3K/AKT信号通路影响HCC细胞系Huh7的细胞周期进程和凋亡. 此外, AIL已被证实是一种有效的雄激素受体(androgen receptor, AR)抑制剂. 它可以直接与p23结合, 抑制AR-热休克蛋白90(heat shock protein 90, HSP90)相互作用, 导致AR蛋白降解, 进而抑制下游基因表达. AIL可下调PKM2和HIF-1α蛋白水平, 阻止PKM2进入细胞核, 并破坏PKM2、HSP90与HIF-1α之间的相互作用, 从而抑制细胞增殖、促进细胞凋亡, 最终阻滞HCC进展.
AIL通过抑制凋亡和调节代谢来阻止HCC肿瘤细胞的生长和增殖. Lin等[121]研究结果表明, AIL可通过直接结合PKM2抑制PKM2, 从而抑制HCC细胞的生长; 它还能抑制PKM2/HSP90/HIF-1α轴和糖酵解, 并促进凋亡. 显示基于AIL的天然产物代谢靶向疗法可能成为HCC的有效治疗方法.
有氧糖酵解最初存在于HCC中, 是肝癌的一个特征, 并负责调节HCC中的增殖、免疫逃避、侵袭、转移、血管生成和耐药. HK2、PFK1和PKM2在HCC中有氧糖酵解的调控中起着重要作用, HK2催化葡萄糖生成6-磷酸葡萄糖, 并能与线粒体外膜上的电压依赖性阴离子通道蛋白1相互作用并结合, 促进ATP的产生并抑制凋亡. PFK1可催化6-磷酸果糖生成1,6-二磷酸果糖, PKM2不仅催化磷酸烯醇式丙酮酸生成丙酮酸, 还可转移到细胞核内, 并作为某些转录因子(如HIF-1α、β-连环蛋白/c-Myc、NF-κB和STAT3)的共激活因子, 促进相关靶基因的转录. 因此, 靶向其通路中的关键因素的抑制作用, 以及调控相关通路, 可能为HCC的治疗提供潜在的新治疗策略. HIF-1α增加关键糖酵解酶, 激活细胞糖酵解, 导致HCC的生长和转移. 在过去十年中, HCC治疗领域经历了范式转变. 这一成功的故事归功于免疫疗法的实. 施和利用联合疗法的新方法. 正在进行的研究具有巨大的前景, 并且在中期HCC中使用联合治疗的前景非常光明. 抗血管生成疗法通过多方面重塑TME, 与PD-1免疫疗法协同作用. 这些药物通过靶向由VEGF过度产生驱动的病理性血管网络, 促进血管正常化, 从而增强效应性T细胞的浸润, 同时减轻缺氧驱动的免疫抑制. 针对血管生成和免疫的HCC研究具有相当大的潜力, 但仍存在重大挑战. 血管靶向治疗面临着对抗血管生成药物的内在和获得性抵抗, 可选择的促血管生成途径的激活, 以及关于血管正常化窗口的未解决的问题, 特别是其短暂性, 最佳治疗时间和监测困难. 整合血管靶向药物和ICIs的联合策略面临双重挑战: 确定最佳协同方案并阐明其机制基础, 以及缺乏有效的预测性治疗效果生物标志物. 如能解决这些挑战将大大改善HCC患者的预后.
总之, 针对HIF-1α而言, 发掘更多的HIF-1α抑制剂抑制HIF-1α基因的表达, 从而降低HIF-1α活性, 起到重塑代谢重编程和肿瘤微环境、抑制肿瘤血管生成、恢复免疫细胞功能等作用, 以提高HCC疗效, 但目前仍是一个挑战. 随着研究的深入开展, HIF-1α抑制剂治疗HCC将带来新的希望, 从而改善HCC预后.
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学科分类: 胃肠病学和肝病学
手稿来源地: 山东省
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科学编辑: 刘继红 制作编辑:张砚梁