Ethinyl estradiol inhibits the progression of gastric cancer by regulating autophagy mediated by CCDC80

Autophagy plays a crucial role in the pathological progression of gastric cancer (GC). However, the roles of autophagy-related genes (ARGs) in GC remain unclear. We performed consensus clustering on 232 ARGs using transcriptomic data, dividing GC patients into distinct molecular subtypes. Differentially expressed gene (DEG) analysis identified 33 prognostic genes that were enriched in autophagy and the MAPK pathway. Additionally, immune infiltration profiling and multi-omics integration analysis (mutation, copy number variation (CNV), and methylation) indicated that CCDC80 was upregulated in GC tissues and correlated with immune infiltration, CNV amplification, and poor prognosis. EE suppressed CCDC80 expression, accompanied by the maturation of cathepsin B (CTSB) and cathepsin D (CTSD), reduced cell invasion and migration, and increased apoptosis. Mechanistically, these effects were associated with inhibition of MAPK pathway activation, while restoration of CCDC80 partially reversed the EE-induced enhancement of autophagy. To validate the therapeutic efficacy of EE against GC in vivo, a xenograft mouse model was established. The results were consistent with those of the in vitro experiments: EE upregulated the expression of autophagy-related proteins by inhibiting MAPK activation, thereby suppressing the growth of GC cells. In summary, our study suggests that CCDC80 is a potential therapeutic target for GC. As an inhibitor of CCDC80, EE may influence GC progression by modulating autophagy through the MAPK pathway, showing promise as a candidate drug for GC treatment. Clinical trial number Not applicable