Qu Xianlin, Liu Bing, Wang Longgang, Liu Luguang, Zhao Weizhu, Liu Changlei, Ding Jishuang, Zhao Siwei, Xu Botao, Yu Hang, Zhang Xiang, Chai Jie
Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China.
Department of Radiology, Shandong University, Shandong Cancer Hospital and Institute, Jinan, Shandong, China; Department of Oncology, Binzhou People's Hospital Affiliated to Shandong First Medical University, Binzhou, Shandong, China.
Drug Resist Updat. 2023 May;68:100936. doi: 10.1016/j.drup.2023.100936. Epub 2023 Jan 31.
Long non-coding RNAs (lncRNAs), as one of the components of exosomes derived from cancer-associated fibroblasts (CAFs), exhibit a crucial role in the pathogenesis and chemoresistance of gastric cancer (GC). Herein, we investigated the role and mechanism of a novel lncRNA disheveled binding antagonist of beta catenin3 antisense1 (DACT3-AS1) and its involvement in GC.
DACT3-AS1 was identified by RNA-sequencing and verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The functional role of DACT3-AS1 in GC was evaluated using in vitro and in vivo experiments including Transwell assay, 5-Ethynyl-2'-deoxyuridine (EdU) assay, immunoblotting, and xenograft tumor mouse model. Dual-luciferase reporter assay was performed to assess the association between genes.
DACT3-AS1 was downregulated and involved in poor prognosis of patients with GC. The results from both in vitro and in vivo experiments showed that DACT3-AS1 suppressed cell proliferation, migration, and invasion through targeting miR-181a-5p/sirtuin 1 (SIRT1) axis. Additionally, DACT3-AS1 was transmitted from CAFs to GC cells mainly via exosomes. Exosomal DACT3-AS1 alleviated xenograft tumor growth. DACT3-AS1 conferred sensitivity of cancer cells to oxaliplatin through SIRT1-mediated ferroptosis both in vitro and in vivo.
CAFs-derived exosomal DACT3-AS1 is a suppressive regulator in malignant transformation and oxaliplatin resistance. DACT3-AS1 could be used for diagnosis and treatment of GC.
长链非编码RNA（lncRNAs）作为癌症相关成纤维细胞（CAFs）来源的外泌体的组成成分之一，在胃癌（GC）的发病机制和化疗耐药性中发挥关键作用。在此，我们研究了一种新型lncRNA——β-连环蛋白3反义1的无序结合拮抗剂（DACT3-AS1）的作用和机制及其在GC中的作用。
通过RNA测序鉴定DACT3-AS1，并通过定量逆转录聚合酶链反应（qRT-PCR）进行验证。使用包括Transwell实验、5-乙炔基-2'-脱氧尿苷（EdU）实验、免疫印迹和异种移植肿瘤小鼠模型在内的体外和体内实验评估DACT3-AS1在GC中的功能作用。进行双荧光素酶报告基因实验以评估基因之间的关联。
DACT3-AS1表达下调并与GC患者的不良预后相关。体外和体内实验结果均表明，DACT3-AS1通过靶向miR-181a-5p/沉默调节蛋白1（SIRT1）轴抑制细胞增殖、迁移和侵袭。此外，DACT3-AS1主要通过外泌体从CAFs传递至GC细胞。外泌体DACT3-AS1减轻了异种移植肿瘤的生长。DACT3-AS1在体外和体内均通过SIRT1介导的铁死亡赋予癌细胞对奥沙利铂的敏感性。
CAFs来源的外泌体DACT3-AS1是恶性转化和奥沙利铂耐药的抑制性调节因子。DACT3-AS1可用于GC的诊断和治疗。
