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

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

  • Drug Resist Updat. 2023 May:68:100936. doi: 10.1016/j.drup.2023.100936.
Xianlin Qu 1,  Bing Liu 1,  Longgang Wang 1,  Luguang Liu 1,  Weizhu Zhao 2,  Changlei Liu 3,  Jishuang Ding 1,  Siwei Zhao 1,  Botao Xu 1,  Hang Yu 1,  Xiang Zhang 3,  Jie Chai 4
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China.
  • 2 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.
  • 3 Department of scientific research project, Shandong Excalibur Medical Research. LTD, Jinan, Shandong, China.
  • 4 Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China. Electronic address: [email protected].
PMID: 36764075 DOI: 10.1016/j.drup.2023.100936
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.

Keywords

DACT3-AS1; Exosome; Ferroptosis; Gastric cancer; Oxaliplatin resistance.

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