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发表于 2008-12-16 15:19:04
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5-3-第三节 肿瘤中的自身抗体
肝细胞癌(hepatocellular carcinoma, HCC)患者中自身抗体的存在状况及其对相关自身抗原的识别已成为令人感兴趣的一个主要研究领域。研究计划最初假设,肿瘤患者产生的自身抗体针对的是细胞从慢性肝病转变为肝癌过程中过表达或异常调节下表达的蛋白。这个假设主要来自对日本慢性肝病患者的追踪研究,这些患者最终都发展为肝细胞癌。HCC在肿瘤中比较独特,因为有可能找到一群经过十年或更长时间后发展成为HCC的癌前期患者。已观察到大约三分之一的HCC患者血循环中有抗某些胞内抗原的自身抗体,而且在这些患者中有一些是由慢性肝病转变为肝细胞癌的,这种转化与出现的新自身抗体相关。有人提出,这些新抗体是对参与恶性变过程的抗原的免疫应答。有实验室用肝细胞癌患者血清中的抗体做免疫筛选,找到了几个令人感兴趣的细胞内蛋白,但本文仅集中描述主要与自身抗原p62相关的新进展。: \8 j7 [" f8 f! Q1 P
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用Western印迹法分析一组来自中国肝细胞癌患者的血清,观察到其中许多血清识别一种分子量大约是62kD的胞质蛋白(p62)。此p62蛋白在肝癌细胞系HepG2和膀胱癌细胞系T24高表达,而在T淋巴细胞株MOLT-4低表达。用一份含高滴度p62抗体患者的血清免疫筛选HepG2和T24细胞cDNA表达文库,分离到了一个全长cDNA克隆。从分析p62蛋白的编码核苷酸序列可知,这是一个从未报道过的新基因。最令人感兴趣的是,发现由此 cDNA推测的p62蛋白的氨基酸序列与mRNA结合蛋白中的一个小蛋白家族高度同源。 9 N) q, r/ a7 R5 X& }% K- ]0 v3 u3 J
B% w7 m; O; Z" u7 T) @, H- I 图5一7描述了p62蛋白及两个相似蛋白ZBP1和Koc的特点,显示出它们独特的RNA结合功能域。该蛋白家族成员的 N端区有RNA识别模体(RRM ),在它的中段到C端有四个hnRNP K同源(KH)结构域。在早期发表的有关p62蛋白的文章中,只报道了1个氨基端RNA识别模体(RRM)和4个KH功能域。但根据用包括BLASTP等最新序列分析程序所作的分析,现已明确在氨基端存在两个RNA识别模体(RRM)。Nielsen和他的同事报道他们已识别出三个相关的人类基因产物,它们是胰岛素样生长因子II (IGF- II)先导肽3mRNA的5’端非翻译区结合蛋白。这些 IGF-II mRNA结合蛋白IMP-1, IMP-2和 IMP-3是在从棒状肉瘤细胞株中分离与IGF-II mRNA结合的蛋白过程中发现的。在发育过程中IMPs的表达受到调控,在胎儿时期表达,在正常成人组织中则检测不到。IMP-1, IMP-2和IMP-3分别由位于17号、3号和7号染色体上的基因各自编码。除了在因共同前体基因转录的差异mRNA剪接所致的KH2和KH3的功能域间插入第43位氨基酸外,IMP-2与p62蛋白完全一样。IMP-3与蛋白Koc相同,是含有肿瘤中过表达的KH结构域的蛋白质,它最初是在胰腺癌和正常组织间的差异显示分析中发现的,Koc在大多数正常组织中不表达。人类的IMP-1与鸡 ZBP-1和小鼠CRD-BP同源。ZBP-1是一种“拉链码(zipcode )”结合蛋白。它最初被认为是结合于β-肌动蛋白mRNA3’端非翻译区(UTR)保守的54核苷酸RNA拉链码(zipcode)元件的蛋白之一,根据需要它被定位于成纤维细胞的前缘。虽然 ZBP-1在肿瘤发生中的作用尚不清楚,但已知它对癌变中起关键作用的细胞迁移来说十分重要。CRD-BP被认为是编码区的不稳定决定簇结合蛋白(the coding region instability determinant bindingprotein),它结合并保护c-myc mRNA,使之免遭内切酶切割,由此延长c-myc在体内的半衰期,这对细胞增殖和肿瘤发生有重要影响。因此,这个家族所有成员的一个共同特征是:它们都是mRNA结合蛋白,结合于不同类型mRNA的5’非翻译区(IMPs)、编码区(CRD-BP)或3’非翻译区(ZBP-1)。必须指出,这些IMPs还可能与其他mRNA结合,所以目前正在进行更多的研究以明确它们在体内的结合特异性。
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0 Z% Q& D/ A! N. g0 z' _& f0 l& M1 N 三种IMPs均与肿瘤有一定关系。IMP-1 /CRD-BP和 IMP-3 /Koc与肿瘤之间可能存在的关系在前面已经作了简短的介绍。IMP-2/p62被认为是一种自身抗原,自身抗体出现在21%的HCC患者体内,但是在慢性肝炎和肝硬化则不出现。免疫组化研究显示,在人的HCC癌结节组织中p62和Koc呈异位表达。IGF-II在许多肿瘤中过表达,最早见到的是它在人HCC的过表达。有一种叫Beckwith Wiedemann综合征的遗传性疾病与IGF- II过表达有关。该综合征表现为巨大内脏和不同脏器的肿瘤。目前已经建立了IGF-II过表达的转基因动物模型,并已导致转基因动物形成肿瘤。在乙肝病毒转基因小鼠,某些小鼠已由慢性肝细胞损伤发展为HCC,在检查包括ras , myc , fos ,abi , src , Rb和p53等大量的癌基因和肿瘤抑制基因其结构和表达是否有异常的过程中,只见到IGF- II呈过表达。4 o, E" f D" X/ f @, l2 r- p2 t
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二、在慢性肝病转变成 HCC的过程中对p62的体液免疫应答
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对有价值的文献复习发现,HBV或HCV相关的慢性肝炎和肝硬化是HCC常见的癌前期疾病,因为它们有可能发展成为HCC,这是HCC的特征之一。在许多国家,HBV和HCV的感染十分普遍。对慢性肝病患者进行有规律的门诊随访治疗,有利于肝癌的早期发现。收集其中一些患者在若干年内的一系列血清样本,以及复习过去报道的研究成果,发现新的自身抗体出现于癌变过程中,而不是在肿瘤前期的慢性肝病阶段。对于HCC来说,发现癌变过程中新的自身抗体以及与其相关的自身抗原的特征,有助于理解胞内蛋白参与癌变的途径。近来分析了一组来自日本17例HCC患者的一组系列血清样本。在慢性肝病转变为HCC的过程中,发现抗p62抗体和抗CENP-F抗体(图5一8)。CENP-F是与着丝粒相关的330kD蛋白,它的表达呈细胞周期依赖性,在分裂间期与核基质有关,在G2期和有丝分裂期CENP-F的表达达到高峰,此时它位于浓聚的染色体的着丝粒上。有一项研究显示,接受随访的36例患者中有22例存在抗CENP-F抗体,而这些人患有包括乳腺癌和肺癌在内的各种肿瘤。这份前瞻性研究提示,癌变可能与自身抗体对胞内某些蛋白的反应相关,而这些蛋白在癌变过程中起一定作用。 4 P7 _' O) x& f+ E' L& w! Z
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三、抗p62和Koc的自身抗体在HCC和其他肿瘤中广泛存在
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1 O1 [% c# v( z! v. e( P 如上所述,在21%的HCC患者体内发现了抗p62抗体,但是作为HCC癌前期疾病的慢性肝炎和肝硬化患者并不出现该抗体。令人感兴趣的是,Koc在胰腺癌和其他肿瘤中有转录性过表达。上述这两种蛋白在结构域和氨基酸序列以及它们与肿瘤的关系等方面都十分相似,这促使对它们进行深入的研究,以确定不同类型的肿瘤患者对这两种蛋白产生的体液免疫反应,并分析被这些自身抗体所识别的p62和Koc中的抗原决定簇的异同。新近研究了在不同类型的恶性肿瘤中抗p62和抗Koc自身抗体出现的范围和频率、抗原中的表位及是否存在交叉反应性抗体。从全长或部分cDNA表达出重组多肽,并将其作为抗原用于免疫印迹法、ELISA和免疫沉淀法检测。在检测到表位后,用重组多肽行交叉吸收以确定血清的特异性。分析了777例十种不同类型恶性肿瘤患者的血清后得出以下结论:11.6%的患者有抗p62抗体,12.2%的患者有抗Koc抗体,累计约有20.5%的患者存在抗这两种自身抗原中之一的自身抗体。这些数值与包括正常人群和自身免疫病患者在内的对照组之间有很大差别。这两种抗原的免疫显性抗原决定簇位于氨基端。吸收试验表明,绝大多数自身抗体不存在交叉反应。抗p62抗体和抗Koc抗体在各种类型的恶性肿瘤中出现的频率大致相当,对它们的免疫应答似乎是相互独立的。
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在以往对系统性风湿病相关自身抗原和相应自身抗体应答意义的研究中,很多研究者揭示了自身抗体的应答主要是由抗原驱使产生的。细胞内抗原诱发自身免疫应答的理由尚未完全弄清,也许基因突变导致了异常蛋白的产生或基因表达的失调,如癌胚蛋白的异位表达。这些情况可能也适合于p62和Koc自身抗体的产生,但是其他机制也应考虑。在不同类型的肿瘤中,抗p62抗体和抗Koc抗体的出现频率和广泛分布与抗p53抗体的出现频率和分布相一致。假如这种现象与这些 mRNA结合蛋白的异常表达有关,那么肿瘤发生的一条途径可能是通过IGF- II表达的失调产生的。对p62和Koc转基因小鼠作深入研究应能帮助我们更好的理解这些蛋白是如何在恶性肿瘤中产生作用的。" R7 Q5 t8 Z- S. q
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在最近的研究中,用免疫组化的方法检测了一组用石蜡包埋保存的HCC组织块,大约三分之一患者的HCC结节高表达p62蛋白,而在相邻的非肿瘤性肝实质细胞内则无异常染色。另外,正常成人肝组织中也检测不到p62。进一步的研究显示,人胎肝脏在 mRNA和蛋白水平均有p62表达,但是在成人肝组织中检测不到或极弱。这些资料与胎儿和成人组织中IMP表达的特点相一致。在肝硬化结节内散布的细胞中检测到了p62表达,而在HCC结节中所有的细胞均检测到p62表达。这些研究显示,在发育过程中p62的表达受到调节,它在胎肝表达,在成人肝脏不表达,而在HCC中呈异常表达。P62可能通过对诸如 IGF- II生长因子表达的调节,在HCC和肝硬化的细胞异常增殖中起重要作用。 4 i- Z& ]. X% }. T9 U' i7 O) u
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系统性自身免疫性疾病中高特异性的自身抗体应答通常预示着疾病的生物学表现型,这使这些自身抗体在临床上更有价值,在诊断中更有意义。许多实验室的研究结果证明,诸如p62/IMP-2, koc/IMP-3、IMP-1、p53和 c-myc等肿瘤相关抗原的自身抗体也许有可能作为肿瘤的标志物。需保留的是抗个别肿瘤特异性抗原的自身抗体达不到能常规地用于诊断所需的敏感水平。随着研究的深入,观察到多种自身抗体的组合能提高疾病诊断的敏感性。可以想像,未来会发现针对肿瘤抗原不同列阵的自身抗体谱,这对肿瘤的诊断将有帮助。
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基于对自身抗体与风湿病发病之间关系的理解,上述对p62和肿瘤的研究提示,对目标脏器中是否存在自身抗原的异常表达做再次检查是有用的。今后的研究目标之一是,检测如干燥综合征这样有明确的靶器官组织且利于评价的疾病其自身抗原谱的表达水平。希望通过检测自身抗体的靶抗原可以更好的理解疾病的发病机制。 8 H. i9 a8 T8 c
( Edward K. L. Chan )! A7 d. q! Q" g% M
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