修回日期: 2011-08-10
接受日期: 2011-10-04
在线出版日期: 2011-10-18
炎胰岛素样生长因子(insulin-like growth factor, IGF)-Ⅱ/IGFⅡ-ⅠR相关信号通路与肝细胞癌(hepatocellular carcinoma, HCC)发生发展密切相关. IGF-Ⅱ活化可经IGF-ⅠR传递促有丝分裂信号, 增加HCC变可能. 近来研究显示靶向IGF-Ⅱ或IGF-ⅠR可明显抑制HCC细胞增殖. 本文就IGF-Ⅱ和IGF-ⅠR信号通路在肝细胞癌变、转化过程中的作用及作为HCC基因治疗靶目标的研究进展进行了评述.
引文著录: 姚登福, 姚敏, 蔚丹丹. IGF-Ⅱ/IGF-ⅠR相关信号通路与肝细胞癌靶向治疗. 世界华人消化杂志 2011; 19(29): 3009-3014
Revised: August 10, 2011
Accepted: October 4, 2011
Published online: October 18, 2011
The insulin-like growth factor (IGF)-Ⅱ/IGF-Ⅰreceptor (IGF-ⅠR) related signaling pathway is associated with the development and progression of hepatocellular carcinoma (HCC). Hepatic IGF-Ⅱactivation can deliver a mitogenic signal to IGF-ⅠR to increase the tumorigenic potential of liver cells. Recently, a considerable amount of evidence suggests that targeted inhibition of IGF-Ⅱ and IGF-ⅠR could inhibit the proliferation of hepatoma cells. In this review, we summarize the interaction of IGF-Ⅱ and IGF-ⅠR in hepatocarcinogenesis and evaluate their potential use in molecular targeted therapy for hepatocellular carcinoma.
- Citation: Yao DF, Yao M, Yu DD. Insulin-like growth factor (IGF)-Ⅱ/IGF-ⅠR related signaling pathway and molecular targeted therapy for hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2011; 19(29): 3009-3014
- URL: https://www.wjgnet.com/1009-3079/full/v19/i29/3009.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v19.i29.3009
肝细胞癌(hepatocellular carcinoma, HCC)是由肝炎病毒(hepatitis B virus, HBV或hepatitis C virus, HCV)感染、化学致癌物等多病因作用, 诱发癌基因或癌相关基因激活、抗癌基因失活或胚胎期某些癌基因重新复活和HCC发生相关信号通路等异常, 致肝细胞恶性转化、增殖失控[1], 经过启动、促进和演变多阶段发病的复杂过程[2,3], 已证明有数百基因表达异常, 调控HCC进展[4,5]. 随着基因(DNA)组学、转录(mRNA)组学和蛋白质组学技术进步, HCC诊治研究有所进展. HCC手术切除仍是最好治疗手段, 但因癌细胞对化疗、放疗不敏感, 其预后极差. 胰岛素样生长因子轴(insulin-like growth factor axis, IGFs)及所介导的信号通路与HCC关系密切, 尤其是该通路的重要成员: IGF-Ⅱ和IGF-Ⅰ受体(insulin-like growth factor-Ⅰ receptor, IGF-ⅠR)至关重要[6-8]. 本文述评IGF-Ⅱ和IGF-ⅠR表达及作为HCC基因治疗靶目标的研究进展.
IGFs有2种相关多肽即IGF-Ⅰ和IGF-Ⅱ, 通过与特异受体IGF-ⅠR和IGF-ⅡR在细胞膜相互作用来发挥活性, 由特异的IGF结合蛋白(insulin-like growth factor binding protein 1-6, IGFBP1-6)和IGFBP水解酶调节, 在细胞生长、增殖、分化、凋亡以及转化方面起着重要作用(表1)[8]. IGF-Ⅱ具有刺激DNA和蛋白质合成, 促进细胞有丝分裂, 调节糖原代谢的作用. 肝组织中IGF-ⅠRmRNA与IGF-ⅡmRNA表达正相关, 可能通过与高亲和力受体IGF-ⅠR结合, 以自分泌和旁分泌方式发挥效应[9,10].
| 相对分子质量 (kDa) | 氨基酸 | 基因定位 | 基因 (kbp) | 外显子 | |
| IGF-I | 7.7 | 70 | 12q22-12q24 | 100 | 6 |
| IGF-Ⅱ | 7.5 | 67 | 11p15 | 30 | 9 |
| IGF-ⅠR | 225 | α: 706; β: 626 | 15q25-15q26 | 100 | 21 |
| IGF-ⅡR | 270 | 2450 | 6q25-6q27 | 140 | 未知 |
| IGFBP-1 | 25.3 | 234 | 7p12-7p14 | 5.2 | 4 |
| IGFBP-2 | 31.4 | 289 | 2q31-2q34 | 32 | 4 |
| IGFBP-3 | 28.7 | 264 | 7p12-7p14 | 8.9 | 5 |
| IGFBP-4 | 26.0 | 237 | 17q12-17q21 | 12 | 4 |
| IGFBP-5 | 28.6 | 252 | 2q31-2q24 | 33 | 4 |
| IGFBP-6 | 22.8 | 216 | 12q13 | 4.7 | 4 |
IGF-ⅠR是细胞表面酪氨酸蛋白激酶受体, 是由2个α亚基(MW为13.5 kDa)及2个β亚基(MW为9 kDa)包含跨膜区、ATP结合位点及酪氨酸激酶区, 以二硫键连接成四聚体. α亚基含有与IGF-Ⅰ或胰岛素结合的位点, 是细胞生长分化的调节因子, 介导丝裂信号、防御凋亡损伤、诱导血管内皮生长因子(vascular endothelial growth factor, VEGF)表达. IGF-Ⅱ是由67个氨基酸残基组成(相对分子质量为7.5 kDa)的单链多肽, 人类IGF-Ⅱ基因位于第11号染色体短臂11p15,其完整的核苷酸序列至少含有9个外显子(E1-E9)及4种启动子(P1-P4). IGF-Ⅱ是调节胚胎生长发育所必需的生长因子之一, 主要由肝脏合成, 在体外具有刺激DNA和蛋白质合成, 促进细胞有丝分裂, 调节糖原代谢的功能[11,12].
IGF-Ⅱ通过其高亲和力受体IGF-ⅠR和IGF-ⅡR以自分泌和旁分泌的方式来发挥效应. IGF-Ⅱ生物学作用主要由IGF-ⅠR介导, 肝细胞IGF-Ⅱ过表达, IGF-Ⅱ与IGF-ⅠR结合后, 解除了α亚基对β亚基上酪氨酸激酶的抑制, 酪氨酸激酶被激活, 自身磷酸化, 导致胰岛素受体底物(ⅠRS)1-4和Shc多位点磷酸化, 启动两条信号级联反应: RAS-RAF-MAPK和PI-3K/AKT/mTOR, 促有丝分裂, 诱导细胞增生、转化和抗凋亡; IGF-ⅠR与胰岛素受体(ⅠR)84%同源, 活化受控于IGF-Ⅱ表达和IGFBP生物活性. 结合PI3-K的调节亚单位P85和生长因子受体结合蛋白2(growth factor receptor binging protein-2, GRB2), 启动两条信号转导通路: PI3K/Akt通路和MAPK通路, 促进细胞有丝分裂, 诱导细胞增生、转化和抑制凋亡. IGF-Ⅱ和IGF-ⅠR表达增多可促进细胞有丝分裂、细胞转化及抗凋亡作用. IGF-ⅡR与转运溶酶体酶结合, 降解IGF-Ⅱ. IGFs的生物活性并不仅仅依赖于他们和IGF受体相互作用, 同时在局部的细胞环境也受IGF结合蛋白的影响[13].
IGFs失衡与肝细胞恶性转化关系密切[14]. IGF-ⅠR和IGF-Ⅱ在胚胎期肝内含量较高, 成人阶段维持低水平[15]. IGF-ⅠR是细胞生长分化的重要调节因子, 可介导丝裂信号、防御凋亡损伤、诱导血管内皮生长因子, 并是一些细胞类型转化所必需[16]. HCC变过程中IGF-Ⅱ/IGF-ⅠR重新激活, 表达增加与分化程度相关. 活化的IGF-Ⅱ/IGF-ⅠR, 具有促进癌细胞播散和侵袭的作用. 以2-乙酰氨基芴制作HCC模型, 观察IGF-Ⅱ和IGF-ⅠR表达与胞内定位, IGF-ⅠRmRNA与IGF-Ⅱ mRNA动态变化. 经病理学证实, 早期肝细胞胞质出现颗粒样变性, 偶见异型胞核; 中期核染色质增粗, 核浆比增大; 后期组织结构消失, 细胞排列成巢状、粗条索状, 细胞核中等大, 核染色质增粗, 核浆比例增大, 均为高分化HCC, 此过程中IGF-Ⅱ和IGF-ⅠR在蛋白和转录水平上呈进行性增加, 伴大量核酸合成, 癌前病变时肝总RNA显著升高, IGF-Ⅱ为重要的细胞生长调节因子, 经IGF-ⅠR酪氨酸激酶途径活化, 在肝细胞异常增殖和分化阶段, IGF-Ⅱ产生胚胎表型逆转, 提示两者的活化、转录与HCC形成有关[17].
胚胎肝内IGF-Ⅱ/IGF-ⅠR过表达, 出生后逐步降至较低水平; HCC变时, 肝IGF-Ⅱ/IGF-ⅠR重新表达, 伴明显的异质性[18,19]. HCCIGF-Ⅱ/IGF-ⅠR基因所编译的肽链与胎肝IGF-Ⅱ/IGF-ⅠR一致. HCC形成多伴有肝炎和/或肝硬化, 且多数伴有HBV感染; 从慢性肝炎到肝硬化到HCC发展过程中, IGF-Ⅱ/IGF-ⅠR表达水平, 癌组织高于肝硬化和/或慢性肝炎的癌周组织(多数伴不典型增生). HCC形成过程中IGF-Ⅱ/IGF-ⅠR变化与肝病理学平行. HCC及HCC细胞株中IGF-ⅠRmRNA和/或蛋白呈过表达, IGF-ⅠR破坏可阻止SV40T抗原或V-ras癌基因诱导转化, 其数量减少则引起转化表型逆转. 相反, IGF-ⅠR过表达导致细胞转化或肿瘤形成, 表皮生长因子受体需经IGF-ⅠR才能对细胞发挥有丝分裂作用及转化潜能, 而IGF-ⅠR过表达直接可引起细胞转化, 对HCC细胞恶性表型建立和维持不可缺少. 在HBV-x阳性HCC细胞株SNU368中, IGF-ⅠR表达显著高于HBV-x阴性HCC细胞株SNU387, 提示HBV-x可通过激活IGF-ⅠR表达参与HCC形成[20].
IGF-Ⅱ及IGF-ⅠR过度表达是HCC形成过程中的重要特征, IGF-ⅠR介导信号传至细胞内, 其异常活化与表达可能是HCC变的早期事件, 机制复杂, 涉及肝炎病毒如HBV和HCV慢性感染与复制、毒素(如酒精或黄曲霉毒素)及代谢产物所致肝损伤与肝硬化, 以及癌基因活化、抑癌基因突变等等. HBV基因编码的HBx蛋白, 可通过蛋白激酶C及p44/p42MAPK信号通路使Sp1磷酸化, 增加其与DNA结合力, 激活IGF-Ⅱ启动子P4, 导致IGF-Ⅱ过表达. HCV核心蛋白也可通过PKC信号通路激活启动子P4, 上调IGF-Ⅱ表达. IGF-Ⅱ/IGF-ⅠR信号途径激活和过表达, 启动下游两条信号级联反应, 促使具有高增殖活性的癌前肝细胞转化、抗凋亡、诱导VEGF表达与新血管生成等[21-24]. HCC组织IGF-ⅠR和IGF-ⅠR-mRNA阳性率分别为80.0%, 76.7%; 非癌组中的表达阳性率分别为43.3%, 33.3%, HCC组阳性率明显高于非癌组, 与HCC动物模型的所测结果相吻合.
培养HCC细胞株(HepG2、Huh-6、Huh-7和PLC), 加入黄曲霉素B1(Aflatoxin B1, AFB1), 发现IGF-Ⅱ和IGF-ⅠR表达与AFB1剂量相关, 提示AFB1经IGF-ⅠR介导信号通路, 促进HCC细胞增殖, 另以含240 mL/L乙醇的流质喂饲野生型小鼠8 wk后, 同样见IGF-ⅠR表达上调. P53可经转录PTEN和IGF-BP3减少IGF-ⅠR/AKT信号途径活化[25]. 突变型P53蛋白丧失了抑癌功能, 密码子249突变的P53蛋白激活相关信号转导通路, 经激活IGF-Ⅱ胚胎型启动子P3和P4, 上调IGF-Ⅱ表达. HCC组织磷脂酰肌醇蛋白聚糖3过表达, 与IGF-Ⅱ或IGF-ⅠR结合, 促其HCC变. 另与IGF-Ⅱ基因低甲基化有关, IGF-Ⅱ基因或启动子中含多个CCGG位点, 正常肝IGF-Ⅱ基因呈高甲基化状态, 而癌组织IGF-Ⅱ呈广泛低甲基化, IGF-Ⅱ基因去甲基化, 使基因重新活化, 肝IGF-Ⅱ过表达引起血IGF-Ⅱ升高[26-28].
HCC治疗以手术为主, 因HCC细胞对放疗、化疗不敏感, 重组DNA技术使HCC基因治疗成为可能, 已成为探讨的热点[29-31]. 非编码RNA(miRNA)是体内的RNA干扰触发器, 可通过在经典的RNA干扰途径降解靶基因mRNA、也可直接抑制靶基因的蛋白翻译、还可经快速脱腺苷化降解mRNA, 被看作体内固有的基因调控子中最大家族. 以真核表达载体构建了IGF-Ⅱ表达干扰载体, 模拟天然miRNA构建表达miRNA质粒, 以调控相关基因IGF-Ⅱ表达, 以人IGF-Ⅱ序列设计并合成miRNA, 将miRNA插入质粒构建pcDNA™6.2-GW/EmGFP miR干扰载体; 经筛选、转染HepG2细胞, 以荧光定量PCR分析靶向HCCIGF-Ⅱ基因表达的干扰效果; 测序证实成功构建真核IGF-Ⅱ干扰质粒MR-IGF-Ⅱ, 将干扰质粒转染至HepG2细胞, 镜下显示50%转染效率; 经荧光定量PCR扩增, 沉默IGF-Ⅱ基因表达效率达43%, 将其转染至HepG2细胞, 在转录和蛋白水平上对IGF-Ⅱ具有较高干扰效率[32].
以调控目标基因的miRNA表达质粒的构建和有效质粒筛选, 确定针对IGF-Ⅱ基因的miRNA的有效作用位点, 选用最有效的并确定了2 035-2 055为IGF-Ⅱ有效位点; 将有效质粒瞬时转染HepG2细胞后, 观察到miRNA使HCC细胞中IGF-Ⅱ表达在转录水平和蛋白水平上都明显下调; 并使HCC细胞增殖受抑制, 表现为细胞周期改变, 癌细胞增殖受阻于G0-G1期, 癌细胞凋亡增加, 证实了IGF-Ⅱ表达与HCC发生的密切关系. 人miRNA干扰质粒能有效抑制HepG2细胞IGF-Ⅱ的表达.针对IGF-Ⅱ表达的相关信号通路的基因治疗或改变IGF-Ⅱ基因启动子P3的甲基化状态, 纠正IGF-Ⅱ基因异常, 可成为基因治疗新靶点[33,34].
HCCIGF-ⅠR过表达[35], 针对IGF-ⅠR分子靶向治疗, 现有多种靶向IGF-ⅠR方法, 如寡核苷酸、单克隆抗体、小分子抑制剂和RNAi等[36-38]. 以靶向IGF-ⅠR的寡核苷酸治疗HCC, 可抑制癌细胞生长、下调IGF-ⅠRmRNA, 注入裸鼠模型, 肿瘤生长受抑, 呈浓度依赖性; 靶向IGF-ⅠR反义寡核苷酸, 能防止HCC复发及HCC肺转移、降低裸鼠血AFP浓度.可阻止激酶域或底物结合位点抑制酪氨酸激酶激活, 靶向IGF-ⅠR的小分子酪氨酸激酶抑制剂颇多, 如酪氨酸磷酸化抑制剂AG538、选择性激酶抑制剂-环木脂体家族的PPP、PQIP、NVP-AEW541和表没食子儿茶素没食子酸酯(epigallocatechin gallate, EGCG)等PQIP为一种新颖有效、选择性的IGF-ⅠR小分子酪氨酸激酶抑制剂, 能有效抑制癌细胞增殖, 与IGF-ⅠR亲和力高于ⅠR的14倍, 因特异性强不影响糖原代谢; EGCG是从绿茶中提取多酚化合物, 可抑制酪氨酸激酶受体(phospho-receptor tyrosine kinase, RTK)和下游信号通路; 提高IGF-ⅠR磷酸化水平, 可诱导癌细胞凋亡、降低IGF-ⅡmRNA及蛋白表达, 与阿霉素联用, 可用于预防或治疗HCC[39,41].
以序列特异性小干扰RNA(siRNA)转染HCC细胞, 使靶mRNA断裂, 经核酸酶作用降解, 目的基因沉默; 靶向IGF-ⅠRmRNA序列siRNA, 脂质体瞬时转染HCC细胞Huh7, 增殖抑制、促进凋亡及使Huh7对阿霉素敏感性增加. 联合应用靶向IGF-ⅠRmRNA及靶向EGFR mRNA的siRNA, 使HepG2和Huh7对阿霉素敏感性增加、下调AKT和ERK磷酸化水平. RNAi可沉默靶基因, 比基因敲除术简单, 与单抗和小分子酪氨酸激酶抑制剂相比不影响ⅠR. 尽管RNAi有巨大治疗潜能, 靶点选择、siRNA导入、沉默基因序列设计、siRNA半衰期延长等尚需更多的研究[42,43].
以IGF-ⅠR单克隆抗体中和IGF-ⅠR, 可阻断IGF-Ⅱ信号转导, 抑制HCC细胞增殖. A12是一种人类单克隆IgG1抗体, 与IGF-ⅠR高度特异, 可促进IGF-ⅠR降解, 阻止与IGF-Ⅱ结合; 在体外可降低IGF-ⅠR和下游信号, 注射人HCC细胞异体移植鼠模型体内, 可延缓肿瘤生长、延长生存期、减少增殖率和诱导凋亡; 单抗分子相对较大, 肽类为抗体小分子片段, 易进入细胞有望成为替代物; 靶向IGF-ⅠR寡肽单抗, 可阻断受体激活及下游信号通路, 可抑制癌细胞增殖.将人抗受体抗体嵌入可下调IGF-ⅠR表达, 而显著抑制受体信号传导[44-46]. 以IGF-ⅠR为靶点的体内试验, 可直接通过诱发凋亡和抑制细胞生长来抑制肿瘤细胞转化和/或使肿瘤消退. 索拉非尼有利于提高晚期HCC患者生存, 但可诱导IGF-ⅠR表达或活化、上调IGF-Ⅱ/IGF-ⅠR途径下游元件(MEK等)发生磷酸化.靶向IGF-ⅠR在HCC治疗中可具有放、化疗增敏作用和联合靶向价值.
HCC发生机制复杂且为多基因疾病, 与肝炎病毒的慢性感染、癌基因及癌相关基因激活及抑癌基因的失活等, 引起肝细胞持续增殖导致癌变[47,48]. HCC发生发展过程中IGF-Ⅱ/IGF-ⅠR信号通路异常激活, 被认为是细胞恶性转化过程的关键[49,50]. 以IGF-Ⅱ特异性反义寡核苷酸治疗或对其启动子进行甲基化处理, 均能抑制肿瘤的生长, 延长动物的存活期. 人源化抗受体抗体的嵌入, 可下调IGF-ⅠR表达, 而显著抑制受体信号传导. 许多体内外肿瘤模型中, 小分子IGF-ⅠR酪氨酸激酶抑制剂对IGF-ⅠR的活性和肿瘤细胞的生长也有明显抑制作用. 而IGF轴与HCC关系复杂, 其确切调控机制有待探讨.
肝细胞癌的防治是全世界的医学难题. 肝细胞癌发展与胰岛素样生长因子轴(insulin-like growth factors, IGFs)及所介导的信号通路与肝细胞癌关系密切, 尤其是该通路的重要成员: IGF-Ⅱ和IGF-Ⅰ受体(IGF-ⅠR)至关重要, 可成为基因治疗新靶点.
田晓峰, 教授, 大连医科大学附属第二医院普通外科; 丁惠国, 主任医师, 首都医科大学附属北京佑安医院肝病消化科; 高润平, 教授, 吉林大学第一医院肝病科
IGF-Ⅱ具有刺激DNA和蛋白质合成, 促进细胞有丝分裂, 调节糖原代谢的作用. 肝组织中IGF-ⅠRmRNA与IGF-ⅡmRNA表达正相关, 可能通过与高亲和力受体IGF-ⅠR结合, 以自分泌和旁分泌方式发挥效应.
以人IGF-Ⅱ序列设计并合成miRNA, 将miRNA插入质粒构建干扰载体; 经筛选、转染HepG2细胞, 将其转染至HepG2细胞, 在转录和蛋白水平上对IGF-Ⅱ具有较高干扰效率.
人miRNA干扰质粒能有效抑制HepG2细胞IGF-Ⅱ表达. 针对IGF-Ⅱ表达的相关信号通路的基因治疗或改变IGF-Ⅱ启动子P3甲基化状态, 与IGF-ⅠR联合干扰效果更佳, 可抑制癌细胞生长, 促进凋亡.
RNAi可沉默靶基因, 比基因敲除术简单, 与单抗和小分子酪氨酸激酶抑制剂相比不影响ⅠR. 尽管RNAi有巨大治疗潜能, 靶点选择、siRNA导入、沉默基因序列设计、siRNA半衰期延长等, 尚需更多的研究.
本文详细论述了IGF-Ⅱ与IGF-ⅠR相关信号通路与HCC发生发展的作用及机制, 就国内外以靶向IGF-Ⅱ或IGF-ⅠR基因治疗在动物体内外抑制HCC现状进行了描述. 题目新颖, 文章层次清楚, 引文全面, 基本反映了本领域最新研究动态
编辑:李军亮 电编:闫晋利
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