Yunyi Liu,Yatao Wu,Changyue Yuan,Bei Hu,Yuxi Xu,Hailong Ou,Juan Li,Dan Qi,Bi Shi,Yiliang Wu,Jason H Huang,Erxi Wu,Xiaoxiao Hu
{"title":"Disruption of the Nucleolin-CXCR4 Interaction by the DNA Aptamer HY-4 Halts Colorectal Cancer Metastasis.","authors":"Yunyi Liu,Yatao Wu,Changyue Yuan,Bei Hu,Yuxi Xu,Hailong Ou,Juan Li,Dan Qi,Bi Shi,Yiliang Wu,Jason H Huang,Erxi Wu,Xiaoxiao Hu","doi":"10.1016/j.ymthe.2025.07.002","DOIUrl":null,"url":null,"abstract":"Colorectal cancer, characterized by its aggressive metastatic behavior and often poor prognosis, urgently necessitates improved diagnostic and therapeutic strategies. This study introduces HY-4, an aptamer developed via a non-SELEX method, which shows exceptional specificity and affinity for nucleolin (NCL), a highly expressed oncogenic protein in various cancers. With remarkable biocompatibility, HY-4 significantly reduces the migration and invasion of LoVo cancer cells by disrupting the NCL-CXCR4 interaction, a pivotal pathway in cancer metastasis. This disruption highlights the potential of HY-4 to inhibit cancer metastasis without producing adverse effects. Notably, HY-4 distinguishes itself from conventional NCL-targeting aptamers by avoiding the typical G-quadruplex structure and instead adopting a unique non-G-quadruplex conformation to create a novel binding site. This unique structural conformation provides critical insight into NCL-targeting mechanisms and could profoundly influence the landscape of targeted cancer therapy. By utilizing advanced techniques such as circular dichroism spectroscopy and molecular docking simulations, we obtained detailed insights into the structural dynamics and inhibitory interactions of HY-4, thereby deepening our understanding of the crucial structure-activity relationships in NCL-targeted drug development. In summary, HY-4 represents a promising advancement in targeted therapy, potentially heralding a paradigm shift in the treatment and diagnosis of colorectal cancer.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"11 1","pages":""},"PeriodicalIF":12.1000,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2025.07.002","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Colorectal cancer, characterized by its aggressive metastatic behavior and often poor prognosis, urgently necessitates improved diagnostic and therapeutic strategies. This study introduces HY-4, an aptamer developed via a non-SELEX method, which shows exceptional specificity and affinity for nucleolin (NCL), a highly expressed oncogenic protein in various cancers. With remarkable biocompatibility, HY-4 significantly reduces the migration and invasion of LoVo cancer cells by disrupting the NCL-CXCR4 interaction, a pivotal pathway in cancer metastasis. This disruption highlights the potential of HY-4 to inhibit cancer metastasis without producing adverse effects. Notably, HY-4 distinguishes itself from conventional NCL-targeting aptamers by avoiding the typical G-quadruplex structure and instead adopting a unique non-G-quadruplex conformation to create a novel binding site. This unique structural conformation provides critical insight into NCL-targeting mechanisms and could profoundly influence the landscape of targeted cancer therapy. By utilizing advanced techniques such as circular dichroism spectroscopy and molecular docking simulations, we obtained detailed insights into the structural dynamics and inhibitory interactions of HY-4, thereby deepening our understanding of the crucial structure-activity relationships in NCL-targeted drug development. In summary, HY-4 represents a promising advancement in targeted therapy, potentially heralding a paradigm shift in the treatment and diagnosis of colorectal cancer.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.