Upregulation of HOXC9 generates IFNγ resistance in gastric cancer by inhibiting DAPK1/RIG1/STAT1 axis.

Clinical reports indicate that gastric cancer (GC) has a high mortality rate, while its pathological mechanism is largely unknown remains poorly understood. This work integrated bioinformatics analysis with experimental verification to explore novel biomarkers of gastric cancer. First, weighted gene co-expression network analysis was applied to screen significant genes correlated with GC development. Besides, gene set enrichment analysis was used to unearth the most relevant biological functions of significant genes. As a result, we firstly 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 interferonγ (IFNγ)-dependent apoptosis in 2 GC cell lines as well as organoids from patients. Furthermore, cleavaed-caspase3/7 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 DAPK1/RIG1/p-STAT1 axis.