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
  • 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.
Products