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

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 po-lymerase 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 in-vasion 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.

Automated summary

In this study, a novel lncRNA called DACT3-AS1 was found to play a crucial role in gastric cancer (GC) by targeting the miR-181a-5p/SIRT1 axis to suppress cell proliferation, migration, and invasion. Additionally, DACT3-AS1 was transmitted from cancer-associated fibroblasts (CAFs) to GC cells via exosomes. Moreover, DACT3-AS1 enhanced the sensitivity of GC cells to oxaliplatin through SIRT1-mediated ferroptosis. Therefore, DACT3-AS1 may serve as a potential diagnostic and therapeutic target for GC.