Endothelial Per-Arnt-Sim domain-containing protein 1 expression is correlated with poor prognosis and promotes invasion and metastasis in gastric cancer.

Background: Gastric cancer (GC) is a leading cause of cancer-related death worldwide. Hypoxia, which is common in solid tumors, contributes to tumor progression. EPAS1, also known as HIF2-α, is a key regulator of cellular responses to hypoxia and is implicated in carcinogenesis. While less studied than HIF1-α is, EPAS1 is overexpressed in various cancers, including GC.

Aim: To assess the relationship between EPAS1 expression and prognosis in GC and investigate its possible role in the development of GC.

Methods: EPAS1 expression in GC and adjacent tissues was assessed using immunohistochemistry. Correlations with clinicopathological features were analyzed by using The Cancer Genome Atlas (TCGA) and clinical data to evaluate its prognostic value. The TIMER2.0 database was used to examine associations between EPAS1 and immune-infiltrating cells. Gene set enrichment analysis identified the mechanisms underlying the role of EPAS1 in GC progression. The relationships between EPAS1 and immunological checkpoints were analyzed in the TCGA-STAD cohort. Cell and animal experiments confirmed the role of EPAS1 in invasion and metastasis.

Results: EPAS1 expression was significantly greater in GC tissues than in adjacent tissues (P < 0.05). High EPAS1 expression was correlated with shorter overall survival (OS) and was associated with greater infiltration depth and poorer tumor differentiation (P < 0.05). Univariate and multivariate Cox analyses revealed that EPAS1 expression (HR: 2.095; 95%CI: 1.019-4.307; P < 0.001) was an independent predictor of OS. EPAS1 was enriched in the epithelial-mesenchymal transition (EMT), inflammatory response, KRAS, TGF-β, TNF-/NF-kB, and IL6/JAK/STAT3 signaling pathways. The high EPAS1 expression group presented increased levels of pathway-related molecules and immunotherapy checkpoints. In vitro and in vivo studies confirmed that silencing EPAS1 reduced GC cell invasion and metastasis.

Conclusion: EPAS1 may be a prognostic marker in patients with GC and may promote tumor growth through the immune response and pathways associated with EMT, inflammatory response, KRAS, TGF-β, TNF-/NF-kB, and IL6/JAK/STAT3 signaling.