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IGF-1受体介导的信号通路与肝癌靶向治疗

2011-03-09姚宁华姚登福

胃肠病学和肝病学杂志 2011年5期
关键词:酪氨酸激酶癌细胞

姚宁华,姚登福

南通大学附属医院临床医学研究中心,江苏南通 226001

肝细胞癌(HCC)是由遗传和表观遗传改变而发生的恶性肿瘤[1],尽管HCC的诊治有所进展,但癌细胞对化疗、放疗不敏感,其预后极差。随着DNA(基因组学)、mRNA(转录组学)和蛋白质(蛋白质组学)技术的进展,正试图探索和开发寻找诊治肝癌的新途径。新颖可靠的早期诊断标志,可预测肝癌发生、鉴定有效靶点,开发靶向治疗药物,以提高肝癌疗效。胰岛素样生长因子家簇(IGFs)在细胞生长、分化、存活、转化、转移及抗癌治疗中扮演重要角色,其作用主要由 IGF-ⅠR介导[2]。在正常肝细胞的恶性转化和癌变过程中,IGF-Ⅱ和IGF-ⅠR表达逐渐增加[3],IGF-Ⅱ生理功能需与IGF-ⅠR结合后才能发挥。近来发现IGF-ⅠR的过表达,既可作为肝癌诊断标志,又是肝癌基因治疗的有效靶目标。本文综述了IGF-ⅠR介导的信号通路在肝癌分子靶向治疗中的研究进展。

1 IGF-Ⅱ/IGF-ⅠR与肝细胞癌变

IGF家族由IGF-Ⅰ和IGF-Ⅱ、2种受体(IGF-ⅠR、IGF-ⅡR)和6种高亲和力的结合蛋白(IGFBP1-6)组成。IGF-ⅠR是位于细胞表面的酪氨酸激酶受体,由2个 α亚基和 2个 β亚基以二硫键相连接组成,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(VEGF)表达[10]。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,受体自身磷酸化,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,加速细胞周期、促有丝分裂,诱导细胞增生、转化和抗凋亡,已证实IGF-ⅠR过表达,可诱导肿瘤形成和转移[11]。IGF-ⅠR活化受控于IGF-Ⅱ表达和IGFBP生物活性,另 IGF-ⅠR激酶活力在细胞内受到Src、整合素、PTP-1、BRACK1支架蛋白影响[3]。

IGF受IGFBPs调节并在IGF-Rs介导下发挥促有丝分裂和调节糖代谢。与正常肝组织相比,癌细胞中IGF-Ⅰ、IGF-Ⅱ和IGF-ⅠR在基因转录和蛋白水平上均上调表达。IGF-ⅠR的作用,受正向调节元件(IGF-Ⅰ和IGF-Ⅱ)和负向调节元件(IGF-ⅡR)影响;正常情况下其表达与活化处在平衡状态,平衡一旦改变,可引起分子级联反应并致癌变[4]。成年鼠肝细胞仅有少量IGF-Ⅰ结合位点,并不认为是活性IGF-Ⅰ主要靶组织;IGF-Ⅱ在胎肝和新生儿肝中大量表达,出生后迅速降低直至关闭;肝细胞癌变过程中IGF-Ⅱ/IGF-ⅠR信号重新激活,IGF-Ⅱ和IGF-ⅠR表达逐渐增加,与肝癌分化程度相关[5,6]。与胰岛素受体(IR)与IGF-ⅠR具有84%同源,与肿瘤进展、增殖和转移相关[7,8]。IGF-ⅠR介导HCC进程中IGF-Ⅱ信号,IGF-Ⅱ/IGF-ⅠR信号途径活化促进癌细胞播散和侵袭行为[9]。

2 肝癌IGF-Ⅱ/IGF-ⅠR表达机制

肝癌恶性程度高,早期发生侵袭血管、局部或远处转移,手术切除率低,发生癌变的分子机制复杂,涉及肝炎病毒如HBV和HCV长期慢性感染与复制、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[12]。IGF-Ⅱ为IGF-ⅠR的高亲和性配体,其异常表达与胚胎型启动子P3和 P4激活、成人型启动子 P1失活有关[13]; HCC组织中IGF-Ⅱ表达与HBV感染相关[14],HBV基因编码的HBx蛋白可激活IGF-ⅠR和IGF-Ⅱ基因表达,通过蛋白激酶C(PKC)及p44/p42MAPK信号通路使Sp1磷酸化,增加其与DNA结合力,激活IGF-Ⅱ基因的启动子P4,导致IGF-Ⅱ过表达[15,16]。P3和P4激活是多数HBV阳性肝癌的重要特征;HCV核心蛋白也可通过PKC信号通路激活启动子IGF-ⅡP4,发挥转录功能,上调IGF-Ⅱ表达。

IGF-Ⅱ通过IGF-Ⅱ/IGF-ⅠR信号途径异常激活和过表达,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。黄曲霉素B1(AFB1)致癌与靶器官DNA修复能力低下相关。在肝癌细胞株(HepG2、Huh-6、Huh-7和PLC)培养过程中,分别加入不同浓度的AFB1,分析AFB1处理前后IGF-Ⅱ和IGF-ⅠR表达变化,发现两者表达与AFB1剂量相关,提示AFB1可经IGF-ⅠR介导的信号通路,促进HCC细胞增殖,至于但AFB1与人类HCC是否相关则有待研究[17]。另以含 24%乙醇的流质喂饲野生型小鼠 8周后,同样见鼠IGF-ⅠR表达上调[18]。

P53可经转录PTEN和IGF-BP3减少IGF-ⅠR/ AKT信号途径活化[19]。P53基因突变与肝细胞癌变密切相关,突变型 P53蛋白丧失了抑癌功能,导致细胞生长调节失控。密码子 249突变的 P53蛋白明显上调IGF-Ⅱ及 IGF-ⅠR,激活信号转导途径,可能经激活IGF-Ⅱ胚胎型启动子 P3和 P4,上调 IGF-Ⅱ表达[20]。左右70%HCC存在磷脂酰肌醇蛋白聚糖3(GPC-3)过表达,分别与IGF-Ⅱ和IGF-ⅠR结合,激活IGF-Ⅱ/ IGF-ⅠR信号,促其肝细胞癌变[21]。

3 IGF-Ⅱ/IGF-ⅠR与肝癌靶向治疗

IGF-Ⅱ及受体IGF-ⅠR过度表达是HCC形成过程中的重要特征[22],IGF-ⅠR介导信号传至细胞内,其异常活化与表达可能是肝细胞癌变的早期事件。近来,证实IGF-ⅠR异常活化和表达与HCC侵袭和转移有关。HCC转移是多步骤的复杂过程,如肿瘤诱导ECM降解、癌细胞进出组织和血管、转移过程中的存活与增殖、器官微环境等,IGFs参与调控[4]。IGF-Ⅱ/ IGF-ⅠR信号可能在促进肿瘤细胞播散和具有侵袭行为时起着关键作用[9]。IGF-ⅠR介导的IGF-Ⅱ信号与HCC恶性表型相关,基质金属蛋白酶2(MMP-2)是IGF-Ⅱ/IGF-ⅠR信号侵袭表型的介质,干扰该信号途径在治疗HCC患者播散转移时具有重要意义。体内研究证实特异性干扰IGF-ⅠR,可抑制肝癌肺转移,也可抑制结肠癌和肺癌的肝转移[23]。

肝癌细胞对放、化疗不敏感,可能与IGF-ⅠR介导信号通路与放、化疗抵抗相关。以RNAi下调IGF-ⅠR表达,可增加结肠癌放、化疗敏感性[24,25]。肝癌细胞对吉非替尼耐药与IGF-Ⅱ/IGF-ⅠR途径异常活化相关[26],索拉非尼有利于提高晚期肝癌患者生存[27],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。异体移植瘤模型证实索拉菲尼联合MEK酶抑制剂—AZD6244治疗HCC比单独使用更为有效[28];雷帕霉素可抑制mTOR途径,与索拉菲尼联合治疗肝癌具协同作用[29]。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。

4 靶向IGF-ⅠR治疗肝癌方法

IGF-ⅠR在肝癌形成、恶性转化及侵袭转移过程中都扮演着重要角色,阻断该信号通路可使癌细胞生长受抑、诱导凋亡,或增加对放、化疗敏感性[30,31]。针对IGF-ⅠR分子靶向治疗,是肝癌生物治疗新的发展方向[32,33],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。

根据碱基互补原则通过人工合成一段与靶基因或其mRNA互补的寡核苷酸片段,与相应靶基因或mRNA特异性结合,干扰基因复制,转录和翻译过程,从而达到削弱或抑制该基因功能的目的。以靶向 IGF-ⅠR的寡核苷酸治疗 HCC体内、外研究显示,该法可抑制癌细胞生长、下调IGF-ⅠRmRNA,但用于全身治疗尚受到如细胞摄取低、缺乏特异靶序列而致非特异毒性反应等限制;以此技术注入裸鼠肝癌模型,其肿瘤生长明显受抑,并呈浓度依赖性。且靶向IGF-ⅠR反义寡核苷酸,能防止肝癌复发及肝癌肺转移、降低裸鼠血AFP浓度[34]。

小分子酪氨酸激酶抑制剂,可阻止激酶域或底物结合位点抑制酪氨酸激酶激活。因IGF-ⅠR和ⅠR激酶区域84%同源、ATP结合位点100%保守,而致IGF-ⅠR酪氨酸激酶抑制剂设计具复杂性。用于靶向IGF-ⅠR治疗肝癌小分子酪氨酸激酶抑制剂颇多(见表1),如酪氨酸磷酸化抑制剂 AG538,但其特异性不够,与ⅠR酪氨酸激酶存在交叉反应;选择性激酶抑制剂—环木脂体家族中的PPP,可有效阻滞IGF-ⅠR活性,且不影响ⅠR;体内、外研究证实PPP能抑制癌细胞增殖[9]。

表1 肝细胞癌治疗中靶向IGF-ⅠR的小分子抑制剂Tab 1 Mo lecu le inhibitors of targeting IGF-ⅠR in treatment of hepatocellular carcinoma

PQIP是一种新颖有效、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[35];嘧啶和足叶草毒素衍生物等有效的抑制剂分子,口服吸收效果好,副作用小;NVP-AEW 541是一种嘧啶衍生物,可抑制Hep3B、HepG2及Huh7生长,促进细胞凋亡[10],可与化疗药物联用[36];表没食子儿茶素没食子酸酯(EGCG)是从绿茶中提取多酚化合物,可抑制酪氨酸激酶受体(RTK)和下游信号通路;提高HepG2细胞IGF-ⅠR磷酸化水平,可诱导癌细胞凋亡、下调信号蛋白(如p-ERK、p-Akt、p-Stat-3和p-GSK-3beta)、降低IGF-ⅡmRNA及蛋白表达,与阿霉素联用,可用于预防或治疗肝癌[37,38]。

IGF-ⅠR单克隆抗体可结合IGF-ⅠR,阻断信号转导,抑制肿瘤生长。鼠源性抗体 αⅠR-3为针对IGF-ⅠRα结构域的单抗,用于治疗人HCC不理想,但在体内外均能抑制癌细胞生长[39]。A12是一种人类单克隆IgG1抗体,与IGF-ⅠR具高度特异性和亲和力,可促进IGF-ⅠR降解,阻止与IGF-Ⅱ结合;前期临床研究显示具广谱抗肿瘤能力,Ⅱ期临床试验初步证实具有临床效率且耐受好;在体外可降低IGF-ⅠR和下游信号;注射到人肝癌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,应用受限;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的信号通路,可抑制癌细胞增殖[40]。

RNA干扰(RNAi)是序列特异性的转录后基因沉默技术,是将序列特异性小干扰RNA(siRNA)转染进细胞,特异性结合或几乎完全互补的靶mRNA并使其断裂,继而在核酸酶作用下被降解,使目的基因沉默;设计靶向IGF-ⅠR mRNA序列siRNA,脂质体瞬时转染肝癌细胞Huh7,明显抑制癌细胞增殖、促进凋亡,并使 Huh7对阿霉素敏感性增加[41]。联合应用靶向IGF-ⅠR mRNA及靶向EGFRmRNA的siRNA,同样能使HepG2和Huh7对阿霉素敏感性增加、并下调AKT和ERK磷酸化水平[42]。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,但将其发展治疗药物还需解决:RNAi靶点选择、siRNA有效的导入。包括针对疾病选择RNAi、沉默基因具体的序列设计siRNA,延长siRNA的体内半衰期、将siRNA导入需要进行基因沉默细胞,将RNAi用于临床治疗HCC尚需研究。

分泌可溶性IGF-ⅠR(sIGF-ⅠR)的肿瘤细胞则丧失了肝转移能力。一种可在体内持续性分泌sIGF-ⅠR的自体骨髓间质细胞,将这些细胞植入小鼠体内,分泌的sIGF-ⅠR在血浆浓度增加,抑制肺癌和结肠癌的肝转移。由此证明:在转移早期,sIGF-ⅠR可以作为诱饵中断IGF-ⅠR的功能;可使用细胞依赖载体持续传递sIGF-ⅠR预防恶性肿瘤肝转移。肝癌中生长因子如HGF、IGFs和Amphyregulin与血管生成基因一样,其异常表达均可能参与肝癌的发生和发展[43]。肝癌细胞转化、增殖、抗凋亡和侵袭的调控通路包括TGF-β/TBR,IGF/IGF-ⅠR、HGF/MET、Wnt/β-catenin/ FZD和TGF-α/EG[44]。

手术切除与肝移植仍然是治疗肝癌最有效方法,近来肝癌切除率虽然有所提高,但 5年生存率改善甚微[45]。肝癌发生发展过程中IGF-Ⅱ/IGF-ⅠR信号通路异常激活,靶向IGF-ⅠR信号途径:因IGF-ⅠR在HCC形成、进展、侵袭和转移中都扮演着角色,在癌前病变阶段靶向IGF-ⅠR治疗;靶向IGF-ⅠR应考虑IGFs因素,如IGFBP3环及IGF-ⅡR抑制基因破坏、IGF-Ⅱ和IGF-ⅡR基因多态性[46],将IGFBPs视为另一抑制IGF-ⅠR法;信号通路是体内分子网络,阻断任何单一通路,可引起其它通路代偿,特异性干扰 IGF-ⅠR也可致EGFR/HER3/AKT通路激活,而影响抗癌效率[47]。

5 展望

肝癌是血供丰富的恶性肿瘤,其发生与肝炎病毒感染、化学致癌物等多病因作用相关,经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合等诸多因素引起肝细胞生长失控而致癌变,历经启动、促进、演变多阶段的发病过程。HCC恶性程度高,进展快;临床就诊时约半数以上患者已属中晚期,丧失手术良机。继证实多激酶抑制剂-索拉非尼有利于提高晚期肝癌患者生存受益[48],联合不同作用途径和机制的药物,多靶点地阻断肝癌细胞的信号传导并抑制其生长;包含靶向IGF-ⅠR的多靶点联合治疗恶性肿瘤被证明有效[49],开展了多项 IGF-ⅠR抗体安全性和有效性临床试验[50],针对 IGF-ⅠR的分子靶向治疗是肝癌生物治疗的重要方向。使用特异性干扰IGF-ⅠR法作持续的探索依然重要,有助于鉴定出最为合理的联合靶向治疗策略。

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