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全球消除HBV母婴传播的进展与挑战
DOI: 10.12449/JCH241104
Advances and challenges in eliminating mother-to-child transmission of hepatitis B virus worldwide
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摘要: 目前，全球89.8%的国家和地区有孕产妇乙型肝炎检测的政策。2022年，全球乙型肝炎疫苗出生接种率、第3剂接种率分别为45%、85%，约3%高病毒载量孕产妇接受了抗病毒治疗，5岁及以下儿童乙型肝炎表面抗原流行率约为0.7%。全球各国乙型肝炎母婴传播取得阶段性进展，但进展差异较大，且面临诸多挑战。全球各地乙型肝炎流行情况、疫苗接种情况、抗病毒药物获取情况不同，此外，实验室检测能力不足、感染孕产妇难以持续获得治疗干预等因素均对消除HBV母婴传播造成了阻碍。
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关键词:
- 乙型肝炎病毒 /
- 传染性疾病传播， 垂直 /
- 疾病消除
Abstract: At present， there are policies for hepatitis B testing in 89.8% of countries and regions around the world. In 2022， the global hepatitis B vaccine birth dose coverage reached 45%， while the third-dose coverage reached 85%. Approximately 3% of pregnant women with high viral loads have received antiviral therapy， and the prevalence rate of HBsAg is about 0.7% among children aged≤5 years. While significant progress has been made in various countries towards eliminating mother-to-child transmission of hepatitis B virus （HBV）， there are still large gaps across countries and numerous challenges. There are differences in the prevalence of hepatitis B， vaccination， and access to antiviral drugs across the globe， and in addition， the factors such as insufficient laboratory testing capacity and difficulties in ensuring sustained access to treatment among pregnant and parturient women with HBV infection pose obstacles to eliminating the mother-to-child transmission of HBV. -
肝细胞癌（HCC）是原发性肝癌中最常见类型，约占80%，位于全球癌症相关死亡原因第4位［1］。目前手术切除［2］和肝移植［3］仍然是肝癌患者主要的根治性治疗方法。但由于HCC早期症状隐匿，大多数患者就诊时已发展至晚期，仅有少部分符合手术切除标准；而肝移植由于供体缺乏以及治疗费用昂贵，令许多患者望而却步。尽管索拉非尼、仑伐替尼和瑞戈非尼等在HCC治疗上的应用令人鼓舞，但耐药性的产生显著降低了其临床疗效。例如，与安慰剂组相比索拉非尼仅可将HCC患者的寿命延长2～3个月［4］。因此，探索HCC耐药机制，寻找合理联合治疗的潜在靶点对改善HCC患者预后至关重要。
自噬在肿瘤细胞耐药过程中具有双重作用。一方面自噬的细胞毒性作用使肿瘤细胞对化疗敏感，导致肿瘤细胞死亡或增殖减少。另一方面自噬作为肿瘤细胞的一种保护机制，可以缓解化疗带来的应激压力，促进肿瘤细胞对化疗药物产生耐药性，从而提高肿瘤细胞的存活率［5］。本文通过总结自噬与HCC耐药的相关性及其机制，为逆转HCC耐药性、提高HCC的治疗效果研究提供参考。
1. 自噬概述
在正常细胞内，自噬是一种细胞内降解的过程，可用于清除衰老或功能失调的细胞器，从而实现细胞内稳态和细胞器的更新。真核细胞中的自噬有3种类型，即巨自噬、微自噬和分子伴侣介导的自噬。巨自噬是由内质网来源的双层膜逐渐包裹降解物后形成自噬小体，然后与溶酶体结合形成自噬溶酶体融化降解其内容物；微自噬是指溶酶体直接吞噬降解物；分子伴侣介导的自噬是细胞内降解物与分子伴侣结合后，被运输到溶酶体内进行降解的过程［6］。
巨自噬（以下简称自噬）是最常见的自噬形式，是促进细胞物质降解和再循环的关键稳态途径［7］。自噬开始的标志是自噬小体的形成，起始过程主要依赖于Unc-51样激酶1（Unc-51-like kinase 1， ULK1）复合物，该复合物包括ULK1、自噬相关基因（autophagy-related gene， ATG）13、ATG101和200 kD的FAK家族相互作用蛋白（FIP200）。在饥饿、缺氧及应激状态下，单磷酸腺苷活化蛋白激酶（AMP-activated protein kinase，AMPK）激活ULK1复合物后，ULK1复合物进一步激活下游Ⅲ型磷脂酰肌醇3激酶（class Ⅲ Phosphatidylinositol 3-kinase，PI3KC3）复合物，即液泡蛋白分选15（vacuolar protein sorting15， VPS15）、VPS34、ATG14和苄氯素1（Beclin1， BECN1），PI3KC3复合物招募微管相关蛋白1轻链3（light chain 3， LC3）泛素样蛋白结合系统及ATG12-ATG5-ATG16复合体，介导形成具有完整双膜结构的自噬体包裹降解物后与溶酶体融合形成自噬溶酶体，自噬溶酶体释放水解酶降解蛋白质和细胞器，从而实现真核生物对细胞内物质的清除及细胞器更新［8］（图1）。
2. 自噬与HCC
自噬在HCC的生长、转移和治疗耐药性中起关键作用。研究［9］表明HCC的自噬过程可抑制细胞凋亡，进而增加肿瘤细胞的存活率并促进肿瘤发展。Wang等［10］的研究表明自噬蛋白ATG5通过介导长链非编码RNA（long non-coding RNA， lncRNA）-ATB/YAP通路促进HCC细胞生长。Huo等［11］对HCC和正常组织进行转录组学数据分析发现，在62个自噬相关基因中有58个基因在HCC中表达上调，其中HDAC1、RHEB和SQSTM1（P62）蛋白的表达水平与药物的半抑制率呈正相关。Lin等［12］的实验表明HCC细胞中自噬生物标志物LC-Ⅱ的水平在索拉非尼耐药的HepG-3细胞中表达显著增加，使用自噬抑制剂3-甲基腺嘌呤（3-methyladenine，3-MA）后可减少LGC-Ⅱ的表达水平，并使索拉非尼的IC50显著下降。同样，Pan等［13］通过全基因组筛查和数据库分析表明溶酶体蛋白跨膜5（lysosomal protein transmembrane 5，LAPTM5）是HCC患者对乐伐替尼耐药的关键因素，其表达量与机体对乐伐替尼的敏感性呈负相关，深入研究相关机制发现LAPTM5可通过促进自噬溶酶体的形成来增加HCC细胞内巨自噬通量，从而对驱动仑伐替尼的耐药性，但使用LAPTM5抑制剂或羟氯喹（抑制自噬小体和溶酶体融合）后可以显著增加仑伐替尼对HCC的敏感性。上述研究表明，自噬标志物表达与HCC耐药呈正相关，靶向自噬的联合治疗可能是克服HCC耐药的一种有前景的策略。
3. 自噬介导HCC耐药的机制
3.1 自噬与上皮间充质转化（epithelial to mesenchymal transition， EMT）途径
EMT是肿瘤发生浸润、转移及耐药的重要机制，主要表现为细胞极性丧失、细胞内连接破坏、侵袭能力增加、N-钙黏蛋白（N-cadherin）、波形蛋白（Vimentin）和锌指蛋白（Snail）水平升高以及E-钙黏蛋白（E-cadherin）降低［14］。国内外研究［15］均表明EMT的异常再激活可增强癌症的化疗和免疫治疗耐药性。HCC的奥沙利铂耐药株与原代株相比出现间充质表型，其上皮标志分子E-cadherin表达下调，提示EMT参与了HCC对奥沙利铂耐药的形成过程。扭曲家族bHLH转录因子1是一种在吉西他滨和索拉非尼无应答的HCC患者中高表达的癌基因，可诱导化疗后的HCC细胞发生EMT［16-17］。同时，转录激活因子3可通过调节HCC细胞自噬并诱导EMT发生，从而介导机体对索拉非尼发生耐药［18］。此外，EMT相关微小RNA（miRNA）与癌症治疗耐药性之间也密切相关。例如，miR-125b、miR-130-3p和miR-375可以通过抑制EMT逆转化疗耐药性，其中miR-125b可抑制细胞自噬使得肿瘤细胞EMT表型丧失，从而克服对奥沙利铂的治疗抵抗作用。相反，miR-27a、miR-32-5p可促进EMT介导多药耐药性［19］。EMT还有助于癌症干细胞群体的形成和维持，而癌症干细胞群体可能与包括HCC在内的多种恶性肿瘤的免疫逃避和治疗耐药性有关［20］。
多项研究显示在HCC中自噬与EMT存在关联。自噬活化cAMP/PKA/CREB通路后可下调上皮标志物表达并上调间充质标志物表达来促进HCC细胞的侵袭，敲低ATG3、ATG7或使用氯喹抑制自噬可阻止cAMP/PKA/CREB信号的传导，并抑制HCC细胞发生EMT［21］。在肿瘤机械微环境中，流体剪切应力（fluid shear stress， FSS）可促进HCC细胞自噬体的形成，并显著增加自噬相关标志物苄氯素1（BECN1）和ATG7的表达。FSS还提高了间充质标志物N-cadherin、Vimentin、 Snail和β-catenin的水平，降低标志物N-cadherin的水平。当使用3-MA或敲低ATG5阻断自噬后，根据E-cadherin、N-cadherin和β- catenin的表达和易位分析发现FSS诱导的EMT发生明显受到抑制［22］。同时，上述研究已证明miR-125b可抑制EMT的发生。然而，调控自噬的跨膜蛋白Eva-1同系物A（EVA1A）在奥沙利铂耐药细胞株中高表达，并能逆转miR-125b对EMT的影响［23］。因此，基于自噬与EMT标志物的关联以及其在HCC耐药性中的作用，靶向自噬可能是治疗HCC的新策略。
3.2 自噬与转化生长因子-β（TGF-β）途径
TGF-β信号通路在各种癌细胞中被激活，并有助于肿瘤的生长和进展［24］。同样，TGF-β表达及其下游转录因子在肝病和HCC中显著升高［25］。TGF-β与受体酪氨酸激酶信号通路之间存在重要的相互作用，这对HCC细胞的存活及其对化疗和检查点阻断剂治疗的耐药性至关重要［26］。研究［27］表明血清中TGF-β1水平升高与晚期HCC患者对索拉非尼和瑞戈非尼的低敏感性有关。同时，Karabicici等［28］通过基础实验也验证了上述结论，并且发现使用TGF-β受体抑制剂可以提高HCC对瑞戈非尼的敏感性。此外，抑制TGF-β1表达还可以降低HCC中PD-L1的表达，并增加其对索拉非尼的敏感性［29］。
自噬和TGF-β通路之间的串扰已在多项研究中得到证实。例如，抑制TGF-β可引起共培养肿瘤细胞中淋巴细胞介导的自噬减少，这表明TGF-β信号在触发自噬过程中发挥重要作用［30］。进一步研究［31］发现TGF-β信号通路通过增强HCC细胞系中BECN1、ATG5、ATG7、DAPK等自噬因子的表达而诱导自噬发生。此外，TGF-β2在诱导细胞自噬的过程中可限制HCC细胞内活性氧（ROS）的产生，进而抑制ROS诱导的细胞凋亡［32］。由此可见，TGF-β与自噬相互作用可直接或间接引起HCC发生耐药，同时阻断自噬和TGF-β信号通路可能成为抗HCC药物研发的新方向。
3.3 自噬与lncRNA途径
lncRNA是一种新型RNA和表观遗传因子，在HCC发生和发展中扮演关键角色。lncRNA能够通过调节癌症相关信号通路中下游基因的表达来促进肿瘤细胞的自噬、增殖和迁移［33］。同时，随着对HCC耐药机制研究的不断深入，越来越多的 lncRNA被发现与HCC耐药相关，其中多种 lncRNA已被证明可以准确预测HCC耐药［34］。表1总结了部分lncRNA在HCC中调节自噬蛋白表达影响HCC耐药及其具体机制的研究。
表 1 自噬和 HCC 耐药中的lncRNATable 1. lncRNA in autophagy and HCC resistancelncRNA 自噬蛋白 细胞 药物 表达状态 主要观点 参考文献 KCNQ1OT1 BECN1 SK-HEP-1
SK-HEP-1/DDP（耐药细胞）
顺铂 在HCC细胞中表达上调 KCNQ1OT1靶向miR-338-3p，抑制SK-HEP-1/DDP细胞的自噬，提高SK-HEP-1/DDP细胞对顺铂的敏感性 ［35］ NEAT1 LC3
ATG3
Huh7
HepG2
索拉非尼 在HCC细胞中表达上调 NEAT1通过调节miR-204/ATG3通路促进HCC细胞的自噬，增强HCC对索拉非尼的耐药性 ［36］ SNGH16 LC3 Hep3B
Hep3B/So（耐药细胞）
索拉非尼 在HCC细胞中表达上调 SNGH16通过下调miR-23b-3p的表达，促进HCC细胞自噬，增加其对索拉非尼的耐药性 ［37］ CRNDE ATG4B SMMC-7721
HepG2
Hep3B
Huh7
索拉非尼 在HCC组织及细胞中表达上调 lncRNA CRNDE通过促进ATG4B的表达介导自噬，增加HCC细胞对索拉非尼的耐药性 ［38］ SNHG1 LC3
BECN1
SR-HCC 索拉非尼 在HCC细胞中表达上调 SNHG1通过上调SLC3A2激活Akt通路，诱导自噬发生，使 HCC对索拉非尼耐药 ［39］ HULC LC3
P62
Hep3B
Huh7
奥沙利铂 在HCC组织及细胞中表达上调 HULC通过调节miR-383-5p/VAMP2轴促进HCC发自噬并减弱HCC对奥沙利铂的化疗敏感性 ［40］ BBOX1-AS1 LC3 Hep3B
Huh7
索拉非尼 在HCC组织及细胞中表达上调 BBOX1-AS1通过调节miR-361-3p/PHF8轴促进细胞自噬，降低索拉非尼在HCC细胞中的细胞毒性 ［41］ HOTAIRM1 BECN1 Huh7
HepG2
仑伐替尼 在HCC组织及细胞中表达上调 HOTAIRM1下调miR-34a激活细胞自噬，诱导HCC对仑伐替尼产生耐药性 ［42］ 注：KCNQ1OT1，KCNQ1重叠转录物1；NEAT1，核富集丰富的转录本1；SNGH16，小核仁RNA宿主基因16；CRNDE，结直肠肿瘤差异表达；SNHG1，小核仁RNA宿主基因1；HULC，肝细胞癌上调长链非编码RNA；BBOX1-AS1，γ-丁酰甜菜碱羟化酶1反义RNA 1；HOTAIRM1，HOXA转录本反义RNA1。
4. 小结与展望
综上所述，HCC耐药是临床上亟待解决的重要问题，自噬在HCC耐药过程中扮演着重要角色，未来有可能是提高顺铂、奥沙利铂、索拉非尼等HCC治疗药物敏感性的重要靶点，但其也是一种重要的细胞保护机制。但自噬在肿瘤发生、发展过程中如何扮演双重角色以及关于自噬诱导HCC耐药过程中如何抑制细胞凋亡的具体机制尚不明确。基于自噬诱导HCC耐药的分子机制，未来研究方向包括抑制自噬作用诱导HCC细胞的凋亡以提高疗效；调节自噬提高抗肿瘤药物对HCC的杀伤效果；通过基因过表达和敲减技术，确定自噬诱导HCC耐药的相关分子靶点。因此，抑制自噬有望成为HCC治疗的新靶标。然而，自噬在HCC治疗抵抗中的作用尚属初步研究，未来需要更多的临床试验加以证实。
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