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Molecular Recognition and In-Vitro-Targeted Inhibition of Renal Cell Carcinoma Using a DNA Aptamer.
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2018-08-04 , DOI: 10.1016/j.omtn.2018.07.015
Hui Zhang 1 , Zhibo Wang 1 , Lin Xie 1 , Yibin Zhang 1 , Tanggang Deng 1 , Jianglin Li 1 , Jing Liu 2 , Wei Xiong 3 , Lei Zhang 4 , Lin Zhang 1 , Bo Peng 1 , Leye He 5 , Mao Ye 1 , Xiaoxiao Hu 1 , Weihong Tan 1
Affiliation  

Renal cell carcinoma (RCC) is the most common malignant tumor of the urinary system, and it has a high frequency of local invasion and distant metastasis. Although multiple advances have been made in the diagnosis and therapy of RCC, the vast majority of patients with metastatic RCC remain incurable. In this study, an aptamer named SW-4 against RCC 786-O cells was identified from a known sequence pool. The identified aptamer exhibited high binding affinity for target cells with dissociation constants in the nanomolar range. Binding analysis revealed that SW-4 only bound to RCC 786-O cells, but not HEK293T cells or human proximal tubular HK-2 cells, indicating that SW-4 has excellent binding selectivity. By sequence optimization, the 26-nt truncated SW-4b demonstrated improved binding affinity, and it was internalized into target cells via caveolae-mediated endocytosis in a temperature-dependent manner. Furthermore, fluorescence imaging confirmed that SW-4b accumulated at tumor sites in 786-O xenograft nude mice models and specifically recognized clinical RCC tissues. Meanwhile, SW-4b inhibited proliferation of 786-O cells by arresting cell cycle progression at the S phase. Taken together, these results indicate that SW-4b is a potential candidate for development into a novel tool for diagnosis and targeted therapy of RCC.



中文翻译:

使用DNA适体对肾细胞癌进行分子识别和体外靶向抑制。

肾细胞癌(RCC)是泌尿系统最常见的恶性肿瘤,其局部浸润和远处转移的频率很高。尽管在RCC的诊断和治疗方面已取得了多项进展,但绝大多数转移性RCC患者仍无法治愈。在这项研究中,从已知序列库中鉴定出了针对RCC 786-O细胞的适体SW-4。鉴定出的适体对靶细胞表现出高结合亲和力,其解离常数在纳摩尔范围内。结合分析表明,SW-4仅与RCC 786-O细胞结合,而与HEK293T细胞或人近端肾小管HK-2细胞不结合,表明SW-4具有出色的结合选择性。通过序列优化,26 nt截短的SW-4b表现出提高的结合亲和力,然后通过小窝介导的内吞作用以温度依赖的方式内化到靶细胞中。此外,荧光成像证实SW-4b在786-O异种移植裸鼠模型和特定识别的临床RCC组织中的肿瘤部位积聚。同时,SW-4b通过在S期阻止细胞周期进程来抑制786-O细胞的增殖。综上所述,这些结果表明,SW-4b是发展成为诊断和靶向RCC的新型工具的潜在候选者。SW-4b通过在S期阻止细胞周期进程来抑制786-O细胞的增殖。综上所述,这些结果表明,SW-4b是发展成为诊断和靶向RCC的新型工具的潜在候选者。SW-4b通过在S期阻止细胞周期进程来抑制786-O细胞的增殖。综上所述,这些结果表明,SW-4b是发展成为诊断和靶向RCC的新型工具的潜在候选者。

更新日期:2018-08-04
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