核酸适配子在肿瘤学研究中的进展

Progress in nucleic acid aptamers for oncology research

单链DNA或RNA可以藉自身形成的三维空间结构与其他各种分子(蛋白质、核酸等)相互作用,以此为基础体外构建随机寡核苷酸文库;然后利用指数级富集的配体系统进化技术(SELEX),通过随机寡核苷酸文库与靶物质结合,经过数轮的筛选和扩增,筛选到与靶物质具有高亲和力特异结合的寡聚核苷酸即为核酸适配子(aptamer)又称核酸配体。适配子具有靶分子范围广,与靶分子结合亲和力高、特异性强的特点。理论上,只要核苷酸库中的序列有足够的多样性,我们可以通过SELEX技术筛选出针对任何靶分子的适配子。核酸适配子的作用机制不同于核酶和反义核酸,而与单克隆抗体类似。通过与靶分子特异结合,核酸适配子可起到识别或抑制靶分子生物学活性的作用。肿瘤的发生发展与许多信号传导途径中的关键蛋白、生长因子及其受体和转录因子表达的改变有密切关系,因此筛选到能与这些蛋白质特异结合的寡核苷酸适配子时肿瘸的诊断和治疗有重要意义。

Nucleic acid aptamers, also termed nucleic acid ligands, are small single-stranded nucleic acids （DNA or RNA）that could directly interact with target molecular by folding into an intricate three-dimensional structure. Aptamers can be isolated from combinatorial libraries by a procedure termed SELEX（systematic evolution of ligands by exponential enrichment）. The SELEX method includes steps of 1）incubating the library with the target molecule; 2）partitioning unbound nucleic acids from those bound specifically to the selector molecule; 3） dissociating the nucleic acid-protein complexes; 4 ） amplifying the nucleic acids pool enriched for specific ligands. Through iterative in vitro selection techniques, aptamers that bind with high affinity and specificity to any target molecule can be generated. Unlike ribozymes and antisense oligonucleotides, aptamers are more similar to monoclonal antibody, having the potential to inhibit the biological function of the molecule resulting in useful reagents for target validation in a variety of disease models. Changes in the expression of key proteins of the cellular signaling pathways, growth factors, receptors, and transcription factors are at the forefront of molecular abnormalities found in cancer, so aptamers that bind with high affinity and specificity to these proteins will be useful in the diagnosis and treatment of cancer.