Loss of cancer-associated fibroblast-derived exosomal DACT3-AS1 promotes malignant transformation and ferroptosis-mediated oxaliplatin resistance in gastric cancer. (May 2023)

• Record Type: Journal Article
• Authors: Qu, Xianlin; Liu, Bing; Wang, Longgang; Liu, Luguang; Zhao, Weizhu; Liu, Changlei; Ding, Jishuang; Zhao, Siwei; Xu, Botao; Yu, Hang; Zhang, Xiang; Chai, Jie
• Is Part Of: Drug resistance updates. Volume 68(2023)
• Publication Date: 2023-05
• Subjects: GC gastric cancer -- lncRNAs long non-coding RNAs -- CAF cancer-associated fibroblast -- CCK-8 Cell counting kit-8 -- EdU 5-Ethynyl-2′deoxyuridine -- qRT-PCR quantitative reverse transcription polymerase chain reaction -- SIRT1 sirtuin1 -- P-gp P-glycoprotein -- BCRP/ABCG2 breast cancer resistant protein/ ATP-binding cassette (ABC) superfamily G member 2 -- RIPA radioimmunoprecipitation assay -- RNase A Riboneclease A -- FBS fetal bovine serum -- FISH fluorescence in situ hybridization -- TME tumor microenvironment -- ceRNA competitive endogenous RNA -- siRNA small interfering RNA -- DLR dual-luciferase reporter -- CM culture medium -- KEGG Kyoto Encyclopedia of Genes and Genomes -- GO Gene Ontology -- miRNA microRNA -- TEM Transmission electron microscopy; Exosome -- DACT3-AS1 -- Gastric cancer -- Oxaliplatin resistance -- Ferroptosis; Drug resistance in cancer cells -- Periodicals; Cancer -- Chemotherapy -- Periodicals; 616.994061
• DOI: 10.1016/j.drup.2023.100936
• Languages: English
• ISSNs: 1368-7646

Abstract

Abstract: Aims: 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. Methods: 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. Results: 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 . Conclusions: 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.