修回日期: 2026-01-10
接受日期: 2026-01-21
在线出版日期: 2026-01-28
信号素(semaphorins, SEMAs)是一种轴突糖蛋白由分泌型或跨膜型相关形式存在, 为多种癌症过程的调节相关分子, 如血管生成、癌细胞侵袭和转移、生长以及癌细胞存活等. 在复杂的SEMAs家族中, 新近发现分泌型的Ⅲ类信号素(class 3 semaphorins, SEMA3s)7成员(SEMA3A-3G)与肝癌进展相关, 并发挥抑制或促进作用, 已引起免疫学及临床医学的极大关注. 本文述评癌相关SEMA3s促进慢性肝病恶性转化机制的研究进展.
核心提要: 信号素(semaphorins, SEMAs)是神经元轴突所需的导向分子, 以分泌型或跨膜型形式存在轴突糖蛋白, 参与肝细胞的恶性转化过程, 与肝细胞癌(hepatocellular carcinoma, HCC)发病率持续增长密切相关, 如组织形态发生、免疫反应和癌症进展. SEMAs家族复杂, 分子中含7叶片的β-螺旋桨结构域. 新近, 发现其家族中分泌型Ⅲ类信号素(class 3 semaphorins, SEMA3s)参与HCC的发生过程, 如在血管生成、癌细胞侵袭和转移、肿瘤生长、癌细胞存活以及免疫学等诸多方面发挥作用. 本文回顾近年HCC及免疫相关SEMA3s的基础和临床研究文献, 述评了肝细胞恶性转化中SEMA3s表达及临床价值.
引文著录: 夏笑笑, 唐昊, 徐敏, 赛文莉, 姚敏, 姚登福. Ⅲ类信号素促进慢性肝病恶性转化机制. 世界华人消化杂志 2026; 34(1): 1-11
Revised: January 10, 2026
Accepted: January 21, 2026
Published online: January 28, 2026
Semaphorins (SEMAs) are axonal glycoproteins that exist in either secreted or trans-membrane forms and are involved in various cancer processes, such as angiogenesis, cancer cell invasion and metastasis, growth, and cancer cell survival. Among the complex SEMAs family, the recently secreted class 3 SEMAs, a seven-member family, have garnered significant attention in immunology and clinical medicine for their dual roles-either inhibiting or promoting-in hepatocellular carcinoma progression. This paper synthesizes the latest advances in understanding how SEMAs promote the malignant transformation of chronic liver diseases.
- Citation: Xia XX, Tang H, Xu M, Sai WL, Yao M, Yao DF. Advances in understanding of role of class Ⅲ semaphorins in promoting malignant transformation of chronic liver diseases. Shijie Huaren Xiaohua Zazhi 2026; 34(1): 1-11
- URL: https://www.wjgnet.com/1009-3079/full/v34/i1/1.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v34.i1.1
肝细胞癌(hepatocellular carcinoma, HCC)仍是全球最常见的肿瘤之一[1]. 以前研究显示[2,3], 乙型肝炎病毒(hepatitis B virus, HBV)或丙型肝炎病毒(hepatitis C virus, HCV)感染是HCC发生最主要的病原学因素. 然而在HBV或HCV感染被有效控制后, HCC发病率仍呈持续增长趋势, 可能与目前迅速增长的代谢功能障碍相关脂肪性肝病(metabolic dysfunction-associated steatotic liver disease, MASLD)发病率密切相关[4]. 肝脏是一个神经支配的器官, 在慢性肝病(chronic liver disease, CLD)进展过程中, 轴突导向线索(axon guidance clues, AGC)分泌信号素(semaphorins, SEMAs), 是神经元轴突所需的导向分子[5]. 在神经系统中广泛表达, 分子复杂, 通过包括受体在内的相互作用吸引或排斥轴[6]. SEMAs为轴突糖蛋白, 以分泌型或跨膜型形式存在, 参与人类组织形态发生、免疫反应及多种肿瘤的进展[7,8]. SEMAs调节恶性肿瘤的血管生成、癌细胞侵袭或远端转移过程, 且在免疫调节中它的分子信号域发挥多种功能[9,10]. 积累的基础研究及临床资料, 证实SEMAs异常表达与良性肝病的恶性转化相关, 然而, 是否可成为监测HCC变化的标志物或HCC基因治疗的分子靶目标, 已引起临床的极大兴趣.
神经系统中广泛表达SEMAs家族, 其分子构成极其复杂, 以一种轴突糖蛋白由分泌型或跨膜型相关形式存在[3]. SEMAs既是神经元轴突所需的导向信号物质, 同时参与人体组织形态、机体免疫及组织癌变等多个过程, 生物学功能强大[2]. SEMAs分子信号结构域的共同特征是含7叶片的β-螺旋桨结构域, 具有与受体结合和特异性的关键残基, 特别是在炎症、肿瘤和自身免疫性等相关疾病中发挥功能[11]. 然而, 新近研究[12,13]发现SEMAs家族成员中的分泌型Ⅲ类信号素(class 3 semaphorins, SEMA3s), 在肝、胃、肺、卵巢、前列腺、乳腺、结直肠和头颈组织等肿瘤发生和进展过程中表达异常, 参与多种癌症过程调节, 如血管生成、癌细胞侵袭和转移、肿瘤生长、癌细胞存活以及免疫学等诸多方面, 并发挥抑制肿瘤生长或促进肿瘤发展的多重作用[14]. 本文回顾国内、外近年有关慢性肝病及机体免疫相关SEMA3s相关基础和临床研究文献, 述评了慢性肝病恶性转化中SEMA3s表达及临床价值.
SEMAs作为轴突导向糖蛋白, 以分泌型或跨膜形式存在, 由一个500个残基的端七叶片β-螺旋折叠结构和共享的保守结构域组成, 由30个基因编码庞大家族[15,16]. 根据结构和氨基酸序列的相似性, SEMAs分为8类: 即无脊椎动物的Ⅰ类和Ⅱ类, 脊椎动物的Ⅲ至Ⅶ类, 以及由病毒基因组编码的Ⅷ类, 其中第Ⅱ类(SEMA2s)、Ⅲ类(SEMA3s)和Ⅷ类(SEMA8s)以分泌型形式存在[17,18], 都包含一个共享的保守结构域和丛状蛋白(plexins, Plex)-SEMAs-整合素结构域, 进行同源二聚体化并绑定到神经嵴蛋白(neuropilins: NP1, NP2)和Plexs等受体[19]. 除了Ⅵ类(SEMA6s), 它们都包含一个"免疫球蛋白样"或"血小板反应蛋白Ⅰ型重复"结构域. SEMAs与跨膜受体如Plexs A1(或A4、B1和D1)-NP1/NP2和整合素相互作用[20,21], 影响下游效应信号通路, 如PI3/AKT、MAPK/ERK等[12,22]. NP1和NP2是具有短细胞质结构域(42-44个氨基酸)和已知信号基序的跨膜糖蛋白, 最后三个氨基酸(S-E-A)通过G-相互作用蛋白参与细胞信号传递. 虽然最初被确定为轴突的关键介质, 但它们现在被认为是血管发生、血管形成和肿瘤生长中发挥重要作用. 此外, 可溶性信号蛋白对NPs具有不同的结合亲和力, 每种蛋白都有独特的生物学功能[13,23], 确切的机制仍需研究.
脊椎动物中有五种SEMAs, 然而, 不同家族之间存在明显的异质性, 这取决于不同癌症的类型[24]. SEMAs在癌症进展过程中发挥调节作用, 如血管生成、组织生长、破骨细胞生成、免疫细胞稳态、多药耐药性、癌细胞侵袭和转移等[2,25]. SEMA3s由七个成员组成, 它们都是可溶性蛋白(分子量为10 kDa, 用A-G表示), 即SEMA3A(或3B、3C、3D、3E、3F和3G)它们由内皮细胞、神经元和肿瘤细胞等细胞系分泌, 并以旁分泌方式影响其他细胞系, 如炎症细胞、血管平滑肌细胞和多种癌细胞[3,25]. 每个成员都包含一个由500个氨基酸残基组成的高度保守的SEMA结构域, 该域与受体和Plex等结合, 介导下游效应细胞信号转导的复合体, 并发挥生物学作用[7,8,26].
SEMA3A优先与NP1结合, 而SEMA3F和SEMA3G对NP的亲和力更强. SEMA3C分为两种类型, 既可与NP1/PlexA1-4结合, 也可与NP2/PlexD1结合, 介导下游效应细胞的信号转导[2,15]. 然而SEMA3E不与NP结合, 而直接与Plex1结合介导下游信号转导[27]. 除SEMA3E外的分泌型SEMA3s与NP类A和D、Plex形成异二聚体进行信号传递, 更具特异性. 可以看出, SEMA3C既与NP1-PlexA1-4结合, 又与NP2-Plex1结合介导下游细胞信号转导. 膜结合Ⅳ类(SEMA4s)-Ⅶ类(SEMA7s)和SEMA3结合并直接激活Plex进行信号转导[28,29]. SEMA7A也以NP作为受体, 在细胞外基质(extracellular matrix, ECM)中进行细胞-ECM的交叉对话, 包括对SEMAs响应的各种交感神经元[30-32], 提示SEMAs可参与其他受损神经支配组织, 如促进慢性肝病的恶性转化.
SEMA3s与受体形成复合物后, 在多种肿瘤中发挥其生物学功能[33]. 最近文献, SEMA3s作用的靶组织及其它们的生物学功能(表1)[9,34-55]. 从表1中可以看出, SEMA3s成员与多种肿瘤进展密切相关[11,19]. 在肿瘤进展中, 可溶性SEMA3s发挥促进或抑制肿瘤进展的生物学功能, 如SEMA3A/3B/3D/3E/3F/3G成员发挥抑癌作用, 影响癌细胞对内皮细胞的粘附、血管通透性, 阻碍肿瘤的发生等; 内皮细胞功能的指导取决于受体复合物, 由于组织特异性表达和共同受体对血管生成的结合; 在肿瘤生长和转移过程中, 通过抑制整合素激活和癌细胞迁移, 另在体内、外研究中, 抑制角细胞存活和索状形成, 具有抗血管生成作用, 可作为潜在的治疗药物[56]. 而SEMA3C是一种血管生成因子, 它诱导基质细胞生长因子表达, 增强内皮细胞的增殖、迁移和粘附, 激活整合素及细胞骨架改变, 诱导血管生成, 表明在多种靶组织中SEMA3C增强, 则发挥促癌作用[57].
| 亚型 | 靶组织 | 生物学功能 | |
| 促癌机制 | 抑癌机制 | ||
| SEMA3A | 乳腺[34] | - | 抑制癌细胞迁移及肿瘤生长 |
| 胃[35] | - | 过表达、减少侵袭和粘附相关 | |
| 卵巢[36] | - | 下调 Lin28B抑制卵巢癌进展 | |
| 肝[37] | 高表达促进HCC形成 | - | |
| SEMA3B | 肝[38] | - | 促癌细胞凋亡和抑癌作用 |
| 乳腺[39] | - | 诱导癌细胞凋亡和抗增殖作用 | |
| SEMA3C | 肝[40] | 重塑微环境、促侵袭和粘附 | - |
| 甲状腺[41] | 激活Wnt/β-catenin通路 | - | |
| 前列腺[42,43] | FOXA1突变、促类固醇生成 | - | |
| 脑[44] | 激活经典Wnt/β-catenin通路 | - | |
| 食道[45] | SOX4-SEMA3C轴促腺癌进展 | - | |
| 结直肠[46] | NP2介导MAPK激活肝转移 | - | |
| 胰腺[47] | 增强癌干细胞, 加速癌转移 | - | |
| SEMA3D | 胰腺[48] | 间接重编程、巨细胞M2极化 | - |
| 甲状腺[49] | - | 调节MAPK/ERK通路抑制增殖 | |
| 肝[50] | - | 抑制PI3K/AKT经FLNA抑癌 | |
| SEMA3E | 骨骼[51] | - | 抑制AMPK和血管生成 |
| SEMA3F | 食道[52] | - | 抑制整合素、粘附, 促凋亡 |
| 肝[53] | AI鉴定, 高表达与HCC相关 | - | |
| 乳腺[54] | - | 经AKT-mTOR和TGFβ信号调节NP-2抑制转移 | |
| 肺[9] | - | 抑制血管生成、基因转录 | |
| SEMA3G | 肾[55] | - | 抑制癌细胞运动、侵袭和增殖 |
SEMA3s调节轴突导向、血管生成、肿瘤生长和肿瘤转移. SEMA3s需要与表面受体NP1或NP2以及Plexs相互作用传递信号. SEMA3B/3F参与肿瘤血管生成、进展和抑制转移, 而SEMA3E抑制肿瘤, 如在结直肠癌、肝转移和黑色素瘤进展中, SEMA3E和PlexD1表达均显著上调[25,55]. 槲皮素为天然黄酮类化合物, 具有抑制肝癌HepG-2细胞、结直肠癌Caco-2细胞和胰腺癌Suit-2细胞的增殖能力, 并通过抗氧化作用, 促进癌细胞凋亡. 在肝癌或胰腺癌细胞中, 它显著调节1307个基因, 最显著的抑制是通过NF2介导的氧化应激反应、糖皮质激素、CDK5和ER/MAPK信号通路, 上调CDKN1A和SEMA3E基因等表达, 下调TOP2A、KIF20A和CCNB1基因表达, 从而发挥其抗肿瘤作用[58].
SEMA3D在胰腺导管腺癌的恶性转化和侵袭中发挥作用. 机制上, 通过KRAS-MUT依赖的ARF6途径间接重编程巨噬细胞, 导致乳酸增加, 乳酸被巨噬细胞上GPCR32感知, 刺激M2型巨噬细胞极化, 促进肿瘤细胞转移[47,48]. 经动物模型验证, 敲除胰腺SEMA3D基因, M2型巨噬细胞减少, 可延迟细胞发生癌变, 延长生存期, 并可防止癌细胞的远处转移. SEMA3D与丝状蛋白A(filamentous protein A, FLNA)相互作用, 使PI3K/AKT信号通路失活, 从而抑制肝癌的进展. 在二乙硝胺诱导的肝癌模型中, SEMA3F的mRNA和蛋白水平均高度表达. 在肾细胞癌组织中, SEMA3G-mRNA低表达, 与临床病理分级高度相关, 患者总生存率较差, 然而, SEMA3G过表达, 可抑制癌细胞增殖、运动和侵袭能力[59]. 因此可见SEMA3s家族成员, 具有促进或抑制肿瘤进展的生物学功能.
分泌型SEMA3s与相应受体(NPs和Plexs)结合发挥其生物学作用. NPs受体为细胞表面糖蛋白, 也是血管内皮生长因子(vascular endothelial growth factor, VEGF)家族成员的共受体[60]; 既参与调控轴突导向和血管生成, 还与癌症进展有关[2,57]. 已证明NPs可控制受体酪氨酸激酶(receptor tyrosine kinases, RTK)所介导的肝细胞生长因子、血小板源性生长因子和表皮生长因子信号通路等[61,62]. 在肿瘤微环境(tumor microenvironment, TME), NPs是调控细胞增殖、肿瘤发生、免疫逃避及转移扩散的关键机制; 临床上, 新抗癌药物与RTK激活靶向癌基因, 一旦耐药性产生, 显著地影响疗效; 而当具有促癌作用SEMA3s与NPs结合后, 致癌信号级联能力增强, 可触发癌细胞逃避细胞毒性T淋巴细胞(cytotoxic T lymphocytes, CTLs)的攻击[63]. 由此可见, 抑制NPs表达或与抗癌药物联合使用, 利于抑制血管生成或癌细胞增殖, 有助于提高抑癌效果.
CTLs虽具有抑制肿瘤进展的潜力, 但受限于组织中免疫抑制的TME和免疫治疗效率[64]. 尽管效应/记忆CD8+T细胞被诱导激活T细胞并出现在循环血液中, 但它们进入癌症组织的能力减弱; 敲除PlexA4基因, CTL可获得更好的淋巴结和肿瘤归巢能力. 在黑色素瘤模型中, 缺乏Plex4的CTLs可延长癌症患者的生存期并改善疗效[65], 如与抗程序性死亡蛋白1(anti-programmed cell death protein 1, 抗PD-1)联合使用时, 疗效更加显著. 临床试验显示, 在黑色素瘤患者的循环CTLs中PlexA4过表达, 但在抗PD-1, 单独或与抗CTLs相关蛋白4治疗后, 尤其是治疗有反应患者中, PlexA4减少, 其机制是通过不依赖于宿主PlexA4配体, 即SEMAs相互作用的细胞自主机制, 负向调控CTLs迁移和增殖, 为以PlexA4为中心免疫治疗铺平道路, 性黑色素瘤血液CTL中PlexA4是监测免疫检查点[66].
作为SEMA3s家族成员, SEMA3F可抑制肺癌细胞生长、侵袭和转移, 且在乳腺癌、结直、卵巢癌、口腔鳞状细胞癌、黑色素瘤和头颈部鳞状细胞癌中, 也具有抗癌作用[67,68]. 基于癌症组图谱(The Cancer Genome Atlas, TCGA)和基因型-组织表达数据, 对SEMA3F表达和预后的泛癌分析, 显示SEMA3F是肝癌的一个潜在的致癌基因. 然而, 肝癌中SEMA3F过表达促进了癌细胞的转移. 通过系列表达和生存分析, 显示了SEMA3F过表达与非编码RNA(noncoding RNAs, ncRNA)之间的关系, 确认了TM-AS1/SNHG16-let-7c-5轴是SEMA3F潜在的上游ncRNA相关途径. 此外, SEMA3F与免疫细胞浸润、免疫细胞和免疫检查点表达呈显著正相关, 且ncRNA介导SEMA3F上调, 与肝癌预后差和肿瘤免疫浸润有关[11,69].
利用单细胞转录组学技术, 对源自原发性黑色素瘤、乳腺癌、肺癌、卵巢癌、结直肠癌和肾癌的脑转移的28421个细胞进行了比较分析, 以确定不同肿瘤中的共同因素, 并揭示促进肿瘤脑转移的关键相互作用[70,71]. 分析血脑屏障的动态变化及其对内皮细胞、周细胞和星形胶质细胞的影响、复杂的细胞间通讯, 并突出星形胶质在TME中的关键作用, 确认VEGF-A、SEMA3E和SPP1途径, 是原发性肿瘤脑转移的关键调节因子, 并影响血管通透性和细胞动力学[72]. 另空间转录组学分析, 也证实了相关通路与TME富集相关. 癌细胞中VEGF过表达, 表明血管生成途径显著激活, 影响血管结构和脑组织, 表明在肿瘤脑转移微环境中, 存在复杂的分子间相互作用. 恢复NK/树突状细胞(dendritic cells, DC)串扰, 强调SEMA3E/PlexD1的重要性, 可有效改善免疫治疗策略[66]. SEMA3S, 在引导轴突方面发挥着关键作用, 在免疫调节方面具有多种功能, 特别是在复杂的炎症和自身免疫性疾病领域. 由此可见, SEMA3s影响免疫过程中T细胞激活、胸腺细胞形成、DC迁移和B细胞增殖等, 提示SEMA3s及其受体, 可作为相关肿瘤诊断标志物或免疫治疗靶点, 具有潜在的应用前景[73].
HCC发生是一个复杂的多因素和多步骤的相互作用过程, 其特征是隐匿发病、高恶性、进展、容易转移和预后不良[1]. 肝脏是一个神经支配的器官, 在CLD进展过程中的AGC分泌, 可以是可溶性或膜结合的蛋白质, 通过相互作用(包括识别受体)吸引或排斥轴突. AGC调节肝纤维化、免疫功能、病毒宿主相互作用和血管生成; 已鉴定出AGC mRNA阳性细胞、蛋白质、调控和预后, 病理特征与局部自主神经系统之间存在紧密的联系[74].
SEMA3A在癌细胞的生物行为和癌症相关巨噬细胞的调节中发挥作用. 对80个肝癌组织和肝癌细胞系的分析表明, SEMA3A过表达与癌细胞的转移潜能呈正相关关系. 用慢病毒感染PLC/PRF/5和HCM3细胞系, 以稳定地上调或下调癌细胞中SEMA3A表达; 体外研究显示SEMA3A过表达促进癌细胞增殖和迁移, 同时凝溶蛋白样帽蛋白、半乳糖凝集素-3、烯醇酶-2和上皮细胞粘附分子表达增加; 在模型小鼠中上调SEMA3A, 通过凝溶蛋白样帽蛋白、半乳糖凝集素-3、烯醇酶-2和上皮细胞粘附分子表达, 促进肝癌进展; 另黄素酮和SM-345431等抑制SEMA3A表达, 显示SEMA3A可成为HCC治疗的潜在靶点[75].
大多数肝癌病例是在纤维化或硬化症下发展, 由于独特的TME、癌症相关成纤维细胞(cancer-associated fibroblasts, CAFs)和癌症干细胞(cancer stem cell, CSCs)之间的复杂相互作用, 它们共同调节肝癌的进展. SEMA3B不同于SEMA3A, 在HCC进展中具有抗凋亡和抗癌作用[76]. 肝癌组织SEMA3B低表达, 且它具有抗癌细胞迁移和侵袭作用. 对132例肝癌患者和57名健康人血液SEMA3B水平的临床分析, 显示肝癌患者血清SEMA3B明显低于健康对照组, 并且与肿瘤大小、包膜、TNM分期呈负相关, 可作为肝癌的预后标志物[77].
位于人类染色体7q21.11上的SEMA3C基因, 编码含有整套特定蛋白构成的结构域, 在细胞信号传导中起关键作用. SEMA3C主要参与神经系统的发育和功能, 指导神经细胞的生长并确保神经网络的形成. 在肝纤维化、癌变组织、血液和索拉非尼耐药肝组织和细胞中, SEMA3C呈显著过表达, 并与癌症干细胞特性相关; NP1和ITGB1是SEMA3C的关键功能体, 激活下游AKT/Gli1/c-Myc信号通路, 以增强肝癌自我更新和肿瘤发生; 促进ECM收缩和胶原蛋白沉积, 并促进肝星形细胞(hepatic stellate cells, HSCs)增殖和激活; 在机制上, HSCs中SEMA3C与NP1和ITGB1相互作用, 激活下游核转录因子(nuclear factor kB, NF-kB)信号, 刺激白细胞介素-6(interleukin-6, IL-6)释放并上调HMGCR表达, 增强HSCs中胆固醇合成. CAFs分泌TGF-β1激活AP1信号, 以增加肝癌细胞中SEMA3C表达, 建立加速肝癌进展正反馈循环. 阻断SEMA3C可有效抑制肿瘤生长, 使肝癌细胞对索拉非尼敏感, 提示SEMAC是HCC进展中促CSCs与间质对话的新标志物, 并有望提高疗效和克服肝癌耐药[78,79].
SEMA3D通过与FLNA相互作用, 抑制PI3K/AKT信号通路, 从而抑制肿瘤生长[50]. SEMA3D在早期胚胎血管发育和多种癌症进展过程中, 调控细胞迁移方面发挥关键作用. 然而, SEMA3D的确切生物学功能有待探讨. 在肝癌组织和细胞系中SEMA3D表达显著下调, 与侵袭性的临床特征和肝癌患者预后不良密切相关. 此外, 肝癌HCCL3细胞系中SEMA3D过表达, 显著抑制了细胞增殖、迁移、侵袭、上皮-间质转化. RNA测序和基因集富集分析表明, SEMA3D干扰肝癌细胞表型和功能, 是由PI3K/AKT信号通路介导; 而免疫共沉淀结合质谱分析表明SEMA3D与FLNA相互作用, 使PI3K/AKT信号通路失活, 通过重塑细胞骨架发挥其抑癌作用, 标明SEMA3D既是一个预后预测因子, 也可能是潜在的治疗靶点[80].
SEMA3E促进肿瘤的侵袭和转移, 取决于PlexD1表达与NP无关. CD4+ CD8+胸腺细胞调控PlxnD1表达. SEMA3E激活PlxnD1和CCR9, 抑制CD6胸腺细胞中CCL25趋化因子信号传导[81]. PlxnD1通过调节趋化因子梯度指导成熟胸腺细胞迁移[82]. 肝癌和胰腺癌细胞系中调控基因1307个, 氧化应激反应、糖皮质激素和ERK/MAPK信号是最突出调控槲皮素对肝癌和胰腺癌细胞生长抑制效应的信号通路. 槲皮素主要是通过调节信号通路和激活CDKN1A、SEMA3E、GADD45B和G45A及下调TOP2A、KIF20A、CCNB2和CCNB1基因实现抗癌作用[58].
肝癌临床病理分期(Ⅰ、Ⅱ和Ⅲ-Ⅳ期)与患者的临床预后密切相关. 在TCGA-LIHC队列中, 通过随机森林、决策树、主成分分析等方法确定的差异基因表达和突变特征分析, 显示肝癌的病理分期有关基因包括GAS2L3和SEMA3F; 与相邻组织相比, 肝癌组织SEMA3F过表达与预后不良有关, 并探讨了临床病理分期中的基因表达和突变特征[83].
白色脂肪和肝组织中SEMA3G过表达. 微阵列分析显示SEMA3G在3T3-L1和小鼠脂肪细胞中, SEMA3G在转录及蛋白水平上调, 促进脂肪细胞分化, 经特异shRNA干预后SEMA3G下调; 鼠高脂饮食模型中, 脂肪组织PI3K/Akt/GSK3β和肝AMPK/SREBP-1c通路激活, 敲低SEMA3G, 体重减轻且肝脂肪和胰岛素抵抗减少, 改善葡萄糖耐受. 肥胖人群中SEMA3G和瘦素水平异常升高, 脂联素浓度降低和胰岛素抵抗, 证实SEMA3G是肥胖脂肪生成和胰岛素抵抗所必需的脂肪因子[84]. 然而, 分泌型SEMA3G, 在HCC中作用机制有待澄清. 由此可见, SEMA3S除神经系统广泛表达, 还参与组织形态、机体免疫功能的调控, 在HCC组织复杂TME中相互作用, 共同调控促进(SEMA3A、C、E和F)或抑制(SEMA3B、和D)癌症进展[85].
机制上, SEMA3s与关键功能受体NP1和ITGB1结合, 激活下游AKT/Gli1/cMyc信号通路, 促进ECM收缩和胶原蛋白沉积、HSCs增殖和激活下游NF-kB信号, 刺激IL-6释放并上调HMGCR表达, 增强胆固醇合成, CAF分泌TGF-β1激活AP1信号, 加速HCC进展. SEMA3s在HCC发生过程中, TME由于CAFs和CSCs间复杂的相互作用具独特性, 作为促进CSCs和间质进行交流, 共同调节, 有助于克服癌细胞耐药性和提高疗效.
目前MASLD患病率正在持续增加, 与2型糖尿病(type 2 diabetes, T2MD)和其他心血管疾病的异常脂代谢有关. 慢性肝病尤其是MASLD相关的SEMAs, 与MASH和肝纤维化的发生关系密切[86]. SEMA3A在肥胖、T2MD和MASLD模型动物的肝窦内皮细胞中升高; 在原代人肝窦内皮细胞中, 加入饱和脂肪酸可诱导SEMA3A表达. 而单个等位基因丢失, 足以减少饮食诱导肥胖鼠肝脂含量[87]. 成年肥胖鼠可诱导血管SEMA3A缺失, 减少肝脂含量, 增加极低密度脂蛋白分泌. SEMA3C是肝硬化组织SEMAs家族中最丰富的成员, 在MASH、酒精性肝炎或HBV所致的肝炎患者中, SEMA3C过表达与肝纤维化关系更密切.
新近研究显示[88]轴突引导分子SEMAs表达, 通过Plexs和NPs信号与HBV引起慢性肝炎及肝纤维化有关. 持续增长的CLD易致纤维化、肝硬化和HCC. TGF-β是激活HSC促进纤维化的关键细胞因子, 可在肝纤维化期间调节TGF-β信号. 在肝纤维化小鼠模型中HSCs激活, 升高的HSCs中SEMA3C缺失, 可减少肌成纤维细胞标志物表达[89]. 相反, SEMA3C过表达加剧TGF-β介导的肌成纤维细胞激活, 如SMAD2磷酸化和靶基因表达增加. 在SEMA3C受体中, 只有NP2可激活HSCs中表达. 有趣的是细胞NP2缺乏减少肌成纤维细胞标志物表达, 特异性激活HSCs中下调SEMA3C或NP2, 可减少小鼠肝纤维化形成[90]. 说明SEMA3C是激活HSCs的新标志物, 在获得肌成纤维细胞表型和肝纤维化中, 发挥至关重要的作用. 前瞻性病例对照研究中, 定量分析95例MASLD患者和35例健康对照者血清SEMA-3A、-3C、4A、-4D、-5A和-7A水平, 在MASLD患者中, SEMA3A、3C和4D浓度显著较高, 而SEMA5A和-7A浓度较低, 但SEMA3C随纤维化阶段显著增加, 而SEMA3A显著减少, 且在预测纤维化方面比FIB-4评分具更好的准确性[32,91]. 另经免疫组织化学证实, MASLD肝中肝细胞、内皮细胞和淋巴细胞中SEMA4D表达较高, SEMA5A rs119222 TT基因型更常见, 且与肝硬度测量值升高相关[90,92], 提示SEMAs与MASLD纤维化相关.
SEMA3C与受体/共受体如PlexA1, -A4, -B1、-D1、-NP1、NP2和整合素相互作用, 影响下游相关的PI3/AKT、MAPK/ERK效应信号通路[93]. 超过90%肝癌病例发生在纤维化或肝硬化条件下, TME由CAFs和CSCs(CD44、CD133)之间的复杂相互作用共同调控[85]. 然而, CSCs在肝癌发展过程中, 如何变化的确切机制尚不清楚. 广泛存在于HCC中SEMA3C, 在调控癌细胞的增殖/存活、新血管生成、癌细胞侵袭或转移、CD44+ CSCs活化和多药耐药形成中发挥重要作用[94,95].
前瞻性多中心队列研究[96], 共纳入321例HBV相关急-慢性肝衰竭(HBV-related acute-on-chronic liver failure, HBV-ACLF)、肝硬化(liver cirrhosis, LC)和慢性乙型肝炎(chronic hepatitis B, CHB)患者, 以正常健康人(normal control, NC)为对照. 并对其中84例外周血单核细胞进行转录分析. 与NC组比较, 显示SEMA6B是HBV-ACLF、LC和CHB患者中最具差异表达的基因. 在测序和外部队列中, 的诊断准确度分别为0.979和0.903. 经ROC分析, HBV-ACLF患者中SEMA6B显著升高, 尤其死亡例. SEMA6B过表达, 主要富集于肝巨噬细胞、肝细胞、炎症和凋亡信号通路. 机制研究显示巨噬细胞中SEMA6B过表达, 加重了患者的炎症反应; 肝细胞中SEMA6B过表达, 使G0/G1细胞周期阻滞, 抑制增殖并诱导细胞凋亡. 然而, 在肝衰竭模型中敲除SEMA6B, 可改善肝功能、减少炎症反应和细胞凋亡, 显著下调炎症相关的信号通路; 以SEMA6B siRNA治疗后, 明显减少肝衰竭的炎症、凋亡并改善了肝衰竭特征. 提示SEMA6B通过巨噬细胞, 介导全身炎症和细胞凋亡加剧肝衰竭, 是HBV-ACLF潜在的有诊断价值标志物. HBV-X可改变长链非编码RNA(long noncoding RNAs, lncRNA)表达谱, 并参与肝癌的进展. 对经病理诊断为HBV相关肝癌和非癌组织, 采用实时定量逆转录聚合酶链反应, 检测肝lncRNA SEMA6A反义RNA1(lncRNA SEMA6A-AS1)表达, 以评估对HBV相关肝癌中的预后价值. 与非癌组相比, 47例HBV相关肝癌组中lncRNA SEMA6A-AS1水平显著下调, 其临床病理学特征与AFP、Edmondson-Steiner分级、肝外转移、包膜侵犯和预后不良显著相关. 此外, 经Kaplan-Meier单因素及Cox回归分析, 均显示lncRNA SEMA6A-AS1低表达与患者总体生存率差, 呈显著相关关系. 提示lncRNA SEMA6A-AS1为HBV相关肝癌患者预后标志和基因治疗的分子靶标[97].
分泌型SEMAs促进慢性丙型肝炎(chronic hepatitis C, CHC)进展, 其表达与CHC患者肝病严重程度相关. 定量检测114例未治疗CHC患者血清SEMAs浓度, 并以36名健康人为对照组(NC). 与NC组比较, CHC患者血SEMA3A、SEMA3C、SEMA5A、SEMA6B和SEMA6D浓度显著升高[98]. 在HCV-G1型和HCV-G3型感染中, 血清SEMA3C和SEMA6D浓度, 与肝纤维化严重程度呈显著正相关关系, 而在HCV两种基因型中, SEMA5A水平与纤维化严重程度呈反比. 经ROC分析, 显示血清SEMA3C>4.0 ng/mL, 诊断准确度为0.8; SEMA6D>4.5 ng/mL, AUC为0.82; 其AUC明显高于肝硬化的APRI评分0.71和FIB-4指数为0.74. CHC患者使用DAA和PEG IFN-α/利巴韦林治疗后, 血清SEMA3C和SEMA6D水平显著下降, 而在DAAs治疗后, 血清SEMA5A浓度显著上升. 免疫组化证实SEMA3C和SEMA5A, 在CHC患者肝硬化肝细胞、内皮细胞和淋巴细胞中表达, 但在NC组无表达, 提示SEMA3C、SEMA5A和SEMA6D为CHC中肝损伤标志物. 分析HCC组与非癌组抑癌型lncRNA SEMA3B-AS1表达, 显示肝癌组lncRNA SEMA3B-AS1表达, 与患者HBV和HCV感染无直接关系. 然而, 低lncRNA SEMA3B-AS1水平与HCC患者预后差密切相关. HCC组lncRNA SEMA3B-AS1与微小RNA(miR-718)表达呈负相关, 与PTEN表达呈正相关关系. HCC细胞lncRNA SEMA3B-AS1过表达致PTEN上调, 而miR-718过表达致PTEN下调. 此外, miR-718过表达减弱lncRNA SEMA3B-AS1表达. lncRNA SEMA3B-AS1和PTEN过表达, 可抑制HCC细胞增殖, 而miR-718则促进HCC生长, 提示miR-18介导lncRNA SEMA3B-AS1和PTEN表达, 以调节肝癌细胞增殖[77].
SEMA3s与多种肿瘤的发展进程相关联, 其生物学功能覆盖血管生成、淋巴管生成、免疫监视和癌症等疾病领域, 在多数情况下为抑制作用; 然而也有少数成员表现出双重调控作用.这种功能取决于与特异受体或不相关受体(如酪氨酸激酶)间结合情况, 以及SEMAs翻译后修饰因素的影响等, 针对SEMAs信号转导级联, 正在开发抗肿瘤或抗血管生成药物, 会成为未来研究的重点方向. SEMA3s是机体免疫反应的关键调节因子, 与免疫细胞浸润、免疫细胞标志和免疫检查点表达显著正相关; 在慢性肝病尤其MASLD相关的SEMA3s, 与MASH、纤维化、癌干细胞活化及肝细胞恶性转化密切相关, 可见SEMA3s为新标志物及治疗性药物靶分子, 深入研究有助于探讨相关肿瘤进展机制, 可为临床干预提供新的分子靶标.
学科分类: 胃肠病学和肝病学
手稿来源地: 江苏省
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科学编辑: 刘继红 制作编辑:张砚梁
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