DNA结合抑制因子在肿瘤靶向治疗中的展望

郭 品 综述 邱永明 审校

(上海交通大学医学院附属仁济医院神经外科,上海 200127)

DNA结合抑制因子(inhibitor of DNA binding,Id)蛋白属于螺旋 -环 -螺旋(helix-loop-helix,HLH)蛋白超家族,为负性调节因子,缺少基本的 DNA结合域,无 DNA结合活性,主要通过螯合广泛表达,见图 1。人类的 Id家族包括四名成员,即 Id-1,Id-2,Id-3,Id-4[1],所有的 Id蛋白拥有高度同源的螺旋环螺旋区域。经过近 20年的研究,它们的细胞和生物学特性已逐渐明了。在细胞分化、凋亡、细胞周期的调节、肿瘤生成、浸润和转移等不同细胞生物学过程中,Id家族各自发挥不同的生物学作用[1-3]。Id基因或蛋白的表达异常,在肿瘤的发生和发展过程中起着重要作用。因此,人为调控 Id基因和蛋白有望成为肿瘤的治疗靶点。本文总结了 Id基因和蛋白在肿瘤发生发展以及预后中的作用,来探讨 Id作为肿瘤治疗有效治疗靶点的可行性。

图1 Id在 bhlh转录作用的模型[1]

1 Id在原发性肿瘤细胞中的表达

正常情况下,Id在成熟的成年正常组织中微量表达,而在多个系统的肿瘤中发现 Id的异常表达[4]。2003年,Lee等[5]在研究肝细胞癌时发现 Id-1可通过 p16INK4a/RB途径来影响肿瘤的发生和发展。之后,在消化系统的其他肿瘤的研究中也发现了 Id的异常。如肝细胞型肝癌中,Id-1在 RNA水平和蛋白水平均存在高表达[5];在原发性结肠癌的研究中,Id-1的表达水平较正常黏膜相比有所升高[6];另外,Shuno等[7]发现,Id-1和 Id-3的异常表达与胰腺癌细胞的转移有关。

同样,在生殖系统肿瘤的研究中也发现 Id基因和蛋白的异常。Id-1在卵巢肿瘤、宫颈癌、乳腺癌、子宫内膜癌以及前列腺癌中的表达异常,并且 Id-1的表达水平与低分化类型、高度的恶性潜能及不良的临床结果有关[8-12];Sablizky等[13]发现在精原细胞癌中,Id家族均高表达。

Id基因和蛋白在中枢神经系统肿瘤的研究较少,但也有发现 Id基因和蛋白表达含量与神经系统肿瘤恶性程度的关系。如在星型细胞肿瘤中,高级别的肿瘤中 Id1-3的表达水平高于低级别的肿瘤[14]。目前 Id基因和蛋白表达含量与神经系统肿瘤患者预后的关系尚未明确。

2 Id参与肿瘤的发生发展

2.1 参与肿瘤血管的生成 血管的生成是肿瘤发生的关节环节之一。已证实,Id-1、Id-3和 Id-4在血管生成方面有促进作用[15,16]。Si等[17,18]在对胃癌的研究中发现,Id-1的过表达可使肿瘤血管的密度增加。另外,在口腔鳞状上皮细胞癌、卵巢癌、子宫颈癌中,也同样发现 Id-1的过表达可能与肿瘤血管的生成有关[8,19,20],其机制尚未明确,有研究者推断可能与 Id-1激活 VEGF有关。在前列腺癌中,Id-1的过表达可激活 VEGF,以提供促进肿瘤血管生成的自分泌信号[21],从而促进肿瘤的发生发展。所以作用于 Id-1,以降低 VEGF的活性,干扰肿瘤血管的生成,达到治疗肿瘤的目的。另外,Volpert等[22]发现,Id-1可通过转录抑制血小板凝血酶敏感蛋白 -1(thrombospondin-1,TSP-1),来调节血管的生成。这无疑又证实了,Id-1可作为肿瘤治疗的靶点。

2.2 抑制肿瘤细胞的凋亡

肿瘤的发生与细胞凋亡的调节紊乱有密切的关系。大量的研究证明,Id家族可影响肿瘤细胞的凋亡。卵巢癌中,Id-1、Id-3蛋白的过表达可激活 E-box,并且可增加细胞周期蛋白依赖性激酶抑制剂(Cyclin-dependent kinase inhibitor,CDKI)的表达水平,抑制抑癌基因的活性,从而抑制细胞的凋亡[23];在乳腺癌细胞中,Id-1可通过 P53和NF-kappaB通路来干预细胞的凋亡[24];在头颈鳞状细胞癌的研究中,Id-1可通过 NF-kappaB/survivin和 phosphoinositIde 3-kinase/Akt信号途径阻止肿瘤细胞的凋亡[25];在肠上皮细胞中,敲除 Id-1和 Id-2可诱导细胞的凋亡,而且 Id-2的过表达可阻止 TGFbeta诱导的凋亡[26];在食管癌中,Id-1可激活 PI3K/Akt/NfkappaB信号通路,抑制细胞的凋亡,还可抑制 TNF-alpha诱导的细胞凋亡[27];Koyama等[28]研究称,在肉瘤细胞系中,Id-3可增强 cddp诱导的细胞凋亡。

另外,Id-1可降低肿瘤细胞对化疗药物的敏感性,从而对抗药物诱导的凋亡。如在膀胱癌中,Id-1的下调可增强肿瘤细胞对表柔比星的敏感性,诱导细胞凋亡[29];Wong等研究称,在前列腺癌细胞系DU145、PC3中,利用 siRNA技术检测到 Id-1的下调,可增加癌细胞对紫杉醇的敏感性,从而促进细胞凋亡[30],其抗药性可能通过 AkT途径来发挥作用[31];鼻咽癌细胞中,Id-1可通过 Raf/MEK通路阻止紫杉醇诱导的细胞凋亡[32]。

由此,我们可以把 Id基因和蛋白作为肿瘤治疗靶点,促进肿瘤细胞的凋亡,从而达到治疗肿瘤的目的。

2.3 调节肿瘤细胞的分化

细胞分化是细胞之间产生差异的过程,细胞的非正常分化,常使得正常细胞瘤变。宫颈癌细胞中,Id-1的过表达可影响细胞分化,从而加速肿瘤的恶性进程[9]。前列腺癌细胞通过 Id-1调节破骨细胞的分化,间接作用于前列腺癌骨转移[33]。在肝脏肿瘤的研究中,Id-1可调节肝细胞瘤细胞的分化,从而加速肝细胞癌变的进程[34]。Kebebew等[35]发现,Id-1基因的过表达可调节甲状腺癌细胞的分化。Id-2在肿瘤的研究较少,但也发现,Id-2可调节乳腺上皮细胞的、肝星形细胞、人类角质化细胞的分化,调控 Id2的表达量,可阻止这些细胞的非正常分化[36-38]。另外,Umetani等[39]发现,Id-4的失活,可与结直肠癌细胞的低分化有关。

可见 Id基因和蛋白在细胞分化中的重要作用,认为调节 Id基因和蛋白的含量,可影响肿瘤细胞的分化,为肿瘤的治疗提供新的思路。

3 Id与肿瘤患者预后的关系

Id的表达的高低,可影响患者的预后。Ding等[40]发现,在乙肝型肝细胞癌患者中,Id-1过表达患者较 Id-1低者的生存时间短,其原因可能与 Id-1的过表达与肿瘤的级别高有关,所以 Id-1可能作为乙肝型肝细胞癌患者预后预测的指标。Tang等[41]在对急性淋巴细胞性白血病患者的研究中发现,Id-1高表达的患者的预后普遍较 Id-1低者差,所以 Tang提出 Id-1可作为急性淋巴细胞性白血病靶向治疗的靶点。在对 Id-2的研究中,也发现 Id-2可影响患者的预后,如 Stighall等[42]发现在原发性乳腺癌患者中,Id-2高表达患者的预后较好,并且有研究证实,在食管上皮细胞癌中,胞浆和胞核均存在 Id-2高表达的患者生存时间较长[43],所以 Id-2也可作为判断预后的一个独立指标。Umetani等[39]在研究结直肠癌时发现,Id-4可作为抑癌基因,从而影响患者的预后。

由此可见,Id可作为影响和判断预后的潜在的标志。这也为我们探讨 Id作为肿瘤治疗的靶点提供了又一有力的证据。

综上所述,Id在肿瘤的发生、发展及对患者预后发挥重要作用。肿瘤的治疗,可考虑从控制 Id基因和蛋白表达水平入手,特别是 Id-1。Id作为高效性和选择性治疗癌症的靶点,有以下原因:①Id蛋白已被证明调解的几个重要基因的活性调控肿瘤的生成和癌症进展[1]。Id蛋白作为调控血管生成、增殖、分化、迁移、侵袭和细胞间相互作用的通路的核心之一。因此,以 Id作为目标可能会同时影响癌症的发展几个不同的方面,可能实现高功效;②Id蛋白在大部分成人的成熟组织中尚未表达[4]。这可能是一种全身治疗的优势,因为大多数正常细胞的功能不会受到影响,从而有可能实现目标的选择性和低毒性。③Id可影响患者预后,认为调控 Id的含量,可延长患者的生存期限。

4 展 望

Id的异常表达可能是一种癌基因的上游或肿瘤抑制基因失调的结果,目前的研究只是停留在推测阶段,其在肿瘤发生发展及预后的作用机制还需要更多的证据支持。每一种靶点的选择都有潜在的优点或者缺点,其可行性和有效性还都需要大量的证据支持。相信随着人类对 Id基因和蛋白越来越多的了解,其作为肿瘤治疗靶点的可行性会得到进一步的证实。接下来,需要的是更深入的研究和更充分的临床证据。

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