Available online 31 January 2023, 100936
Author links open overlay panelAbstractAimsLong 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.
MethodsDACT3-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.
ResultsDACT3-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.
ConclusionsCAFs-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.
AbbreviationlncRNAslong non-coding RNAs
CAFcancer-associated fibroblast
EdU5-Ethynyl-2’deoxyuridine
qRT-PCRquantitative real-time polymerase chain reaction
BCRP/ABCG2breast cancer resistant protein/ ATP-binding cassette (ABC) superfamily G member 2
RIPAradioimmunoprecipitation assay
FISHfluorescence in situ hybridization
TMEtumor microenvironment
ceRNAcompetitive endogenous RNA
siRNAsmall interfering RNA
DLRdual-luciferase reporter
KEGGKyoto Encyclopedia of Genes and Genomes
TEMTransmission electron microscopy
KeywordsExosome
DACT3-AS1
Gastric cancer
Oxaliplatin resistance
Ferroptosis
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