Effect and mechanism of the miR-1284/EIF4A1 axis on the cGAS-STING pathway under radiotherapy

Background: Gastric Cancer (GC) remains a major global health concern, with limited treatment options, especially in advanced stages. Radiotherapy (RT) plays a vital role in GC management, but resistance to DNA damage impedes its effectiveness. MicroRNA-1284 (miR-1284), a tumor suppressor, regulates eukaryotic translation initiation factor 4A1 (EIF4A1), which is involved in DNA damage repair through homologous recombination (HR). This axis has been implicated in enhancing GC cell survival following RT. Additionally, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, activated by DNA damage, plays a key role in triggering an anti-tumor immune response. However, the interaction between the miR-1284/EIF4A1 axis, DNA repair, and the cGAS-STING pathway in GC under RT conditions remains unclear. This study aims to investigate how the miR-1284/EIF4A1 axis influences DNA repair and its role in activating the cGAS-STING pathway to enhance RT efficacy in GC.

Methods: A stably expressed messenger miR-1284 cell line was established. Quantitative reverse transcription and western blot were used to examine the expression of miR-1284 and EIF4A1, and the effect of blocking the miR-1284/EIF4A1 axis on the cGAS-STING pathway and interferon-β (IFN-β) in GC cells after RT; cytotoxicity experiments were conducted to explore the mechanism of the miR-1284/EIF4A1 axis in radiation-induced DNA damage repair; animal experiments were conducted to explore the translational application of rocaglamide (RocA) combined with the programmed cell death-ligand 1 (PD-L1) antibody in RT.

Results: The miR-1284/EIF4A1 axis in the GC cells promoted the repair of radiation-induced DNA damage and was associated with the prognosis of GC patients. Blocking this axis delayed the C-terminal binding protein interacting protein (CtIP)-mediated DNA repair, enhanced RT effectiveness, and activated the cGAS-STING pathway, while increasing the rate of Apoptosis. In vivo experiments based on RocA binding to PD-L1 antibodies under RT had good biological safety, and thus provide a potential therapeutic strategy for the treatment of GC.

Conclusions: The miR-1284/EIF4A1 axis promotes the repair of DNA damage caused by RT, promotes the activation of the cGAS-STING pathway in GC, and has good biological safety. Our findings provide an important experimental basis for enhancing the anti-tumor immune effect of RT in the treatment of GC.

Gastric cancer (GC); cyclic GMP-AMP synthase-stimulator of interferon genes pathway (cGAS-STING pathway); microRNA-1284/eukaryotic translation initiation factor 4A1 axis (miR-1284/EIF4A1 axis); radiotherapy (RT).