Qian Na, Huang Tongtong, Zhang Lulu, Zhang Li, Zhou Lijie, Wang Dong, Liang Xiao, Fu Songbin, Xue Yingwei, Yu Jingcui
Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150081, China.
Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, 150081, China.
Sci Rep. 2025 Jul 25;15(1):27089. doi: 10.1038/s41598-025-12789-8.
Circular RNAs (circRNAs) are highly stable and abundant in tumor-derived exosomes, where they often function as microRNA (miRNA) sponges to regulate gene expression and biological processes. Previous research showed that Transducer of ERBB2.1 (TOB1) overexpression induces autophagy and suppresses gastric cancer progression through exosome secretion. This study investigates the relationship between TOB1, exosomal circRNAs, and their target miRNAs in gastric cancer. RNA sequencing and bioinformatics analyses identified differentially expressed circRNAs and miRNAs in exosomes from gastric cancer cells. qRT-PCR revealed that hsa_circ_0008719 was downregulated in gastric cancer tissues compared to normal tissues. Further analysis showed that TOB1 upregulates hsa_circ_0008719 and downregulates miR-3615 in gastric cancer cells and their exosomes. Functional assays, including lentiviral infection, Cell Counting Kit-8 (CCK-8), colony formation, and Western blot, demonstrated that exosomal hsa_circ_0008719 inhibits proliferation and promotes autophagy in gastric cancer cells. Differential expression analysis identified 87 upregulated circRNAs and 1 upregulated miRNA, as well as 2 downregulated circRNAs and 8 downregulated miRNAs in exosomes from TOB1-overexpressing AGS cells. Twelve novel circRNAs were discovered. GO and KEGG analyses linked the host gene of hsa_circ_0008719, AKT2, to gastric cancer and autophagy pathways. hsa_circ_0008719 was found to localize in the cytoplasm, where it binds to miR-3615. These findings highlight the TOB1-hsa_circ_0008719-miR-3615 axis in gastric cancer, showing that exosomal hsa_circ_0008719 suppresses cancer progression by enhancing autophagy and reducing proliferation. This study provides insights into the role of TOB1-mediated exosomal circRNAs in gastric cancer regulation.
环状RNA（circRNAs）在肿瘤来源的外泌体中高度稳定且含量丰富，它们常作为微小RNA（miRNA）海绵发挥作用，以调节基因表达和生物学过程。先前的研究表明，ERBB2.1转导蛋白（TOB1）的过表达通过外泌体分泌诱导自噬并抑制胃癌进展。本研究探讨了TOB1、外泌体circRNAs及其靶标miRNA在胃癌中的关系。RNA测序和生物信息学分析确定了胃癌细胞外泌体中差异表达的circRNAs和miRNAs。qRT-PCR显示，与正常组织相比，hsa_circ_0008719在胃癌组织中表达下调。进一步分析表明，TOB1在胃癌细胞及其外泌体中上调hsa_circ_0008719并下调miR-3615。包括慢病毒感染、细胞计数试剂盒-8（CCK-8）、集落形成和蛋白质印迹在内的功能分析表明，外泌体hsa_circ_0008719抑制胃癌细胞增殖并促进自噬。差异表达分析确定了过表达TOB1的AGS细胞外泌体中有87个上调的circRNAs和1个上调的miRNA，以及2个下调的circRNAs和8个下调的miRNAs。发现了12种新的circRNAs。基因本体（GO）和京都基因与基因组百科全书（KEGG）分析将hsa_circ_0008719的宿主基因AKT2与胃癌和自噬途径联系起来。发现hsa_circ_0008719定位于细胞质中，并在那里与miR-3615结合。这些发现突出了胃癌中的TOB1-hsa_circ_0008719-miR-3615轴，表明外泌体hsa_circ_0008719通过增强自噬和减少增殖来抑制癌症进展。本研究为TOB1介导的外泌体circRNAs在胃癌调控中的作用提供了见解。
