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Clinical reports indicate that gastric cancer (GC) has a high mortality rate, but its pathological mechanism remains poorly understood. This work integrated bioinformatics analysis with experimental verification to explore novel biomarkers of gastric cancer. First, weighted gene coexpression network analysis was applied to screen significant genes correlated with GC development. Gene set enrichment analysis was also used to unearth the most relevant biological functions of significant genes. As a result, we discovered homeobox C9 ( HOXC9 ) as a novel oncogene in GC, primarily through negatively regulating immune response. High expression of  HOXC9  predicted a poor prognosis in GC patients, and knocking down  HOXC9  efficiently enhanced the interferon‐gamma (IFNγ)‐dependent apoptosis in two GC cell lines as well as organoids from patients. Furthermore, cleaved caspase‐3/7 and phosphorylated signal transducer and activator of transcription 1 (p‐STAT1) were also significantly enhanced in  HOXC9  knockdown cells and organoids treated with IFNγ. Mechanistically, we found that  HOXC9  inhibited the death‐associated protein kinase 1 ( DAPK1 ) and its downstream retinoic acid‐inducible gene‐I ( RIG1 ) to generate GC IFNγ resistance. In summary, we identified and confirmed that  HOXC9  generates IFNγ resistance in GC by inhibiting the  DAPK1/RIG1/p‐STAT1  axis.

Upregulation of HOXC9 generates interferon‐gamma resistance in gastric cancer by inhibiting the DAPK1/RIG1/STAT1 axis