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

Elsevier

Available online 31 January 2023, 100936

Drug Resistance UpdatesAuthor links open overlay panelAbstractAims

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.

AbbreviationlncRNAs

long non-coding RNAs

CAF

cancer-associated fibroblast

EdU

5-Ethynyl-2’deoxyuridine

qRT-PCR

quantitative real-time polymerase chain reaction

BCRP/ABCG2

breast cancer resistant protein/ ATP-binding cassette (ABC) superfamily G member 2

RIPA

radioimmunoprecipitation assay

FISH

fluorescence in situ hybridization

TME

tumor microenvironment

ceRNA

competitive endogenous RNA

siRNA

small interfering RNA

DLR

dual-luciferase reporter

KEGG

Kyoto Encyclopedia of Genes and Genomes

TEM

Transmission electron microscopy

Keywords

Exosome

DACT3-AS1

Gastric cancer

Oxaliplatin resistance

Ferroptosis

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© 2023 Published by Elsevier Ltd.

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