Jumonji domain-containing protein 6 promotes gastric cancer progression: Modulating immune evasion through autophagy and oxidative stress pathways.

Abstract

Objective: Immune response is crucial in the development of gastric cancer (GC), and Jumonji domain-containing protein 6 (JMJD6) plays an important role in mediating GC cell behavior. This study aims to elucidate the mechanisms through which JMJD6 affects autophagy and immune evasion in GC cells.

Material and methods: Immunocytochemistry was employed to assess JMJD6 and programmed death-ligand 1 (PD-L1) levels in gastric cancer cell line (MKN-45) and gastric epithelial cell line cells. MKN-45 cells with JMJD6 knockdown and overexpression were generated. The effect of JMJD6 on MKN-45 cells was evaluated using cell counting kit-8 assay, cellular fluorescence staining, and Transwell assays. Western blot analysis and immunofluorescence techniques were employed to investigate the regulation of autophagy by JMJD6. Reactive oxygen species (ROS) levels were evaluated by applying ROS fluorescence staining. Meanwhile, the protein and gene expression levels of molecules related to antioxidant stress responses were assessed through immunofluorescence assays and quantitative real-time polymerase chain reactions, respectively.

Results: The expression levels of JMJD6 and PD-L1 were elevated in GC cells (P < 0.001). JMJD6 overexpression enhanced MKN-45 cell migration, invasion, and colony formation in vitro (P < 0.001). In MKN-45 cells, the epithelial-mesenchymal transition was promoted by JMJD6 upregulation but was notably inhibited by JMJD6 knockdown (P < 0.001). JMJD6 overexpression increased the expression levels of Sequestosome 1, Microtubule-associated protein 1A/1B-light chain 3 (LC3)II/LC3I, and PD-L1 in MKN-45 cells, and autophagy activation further elevated PD-L1 levels (P < 0.001). In addition, JMJD6 overexpression reduced ROS production and increased the expression of molecules related to antioxidant stress response, with the reverse effects observed on JMJD6 knockdown (P < 0.001).

Conclusion: JMJD6 notably facilitates GC progression and immune evasion by modulating autophagy and oxidative stress pathways.