Investigating the impact of Sprouty-related EVH1 domain-containing protein 3 on gastric cancer prognosis and tumor microenvironments

Abstract

Introduction Gastric cancer is a prevalent and lethal malignancy, yet effective biomarkers remain limited. SPRED3 has been implicated in other cancers, but its role in gastric cancer has remained completely unexplored. Methods SPRED3 expression and clinical significance were analyzed using TCGA and GEO datasets. Knockdown experiments were performed in AGS and N87 gastric cancer cell lines to assess effects on proliferation (CCK-8), migration, and invasion (Transwell). Pathway changes were examined by Western blot and qRT-PCR. Immune infiltration was evaluated via CIBERSORT and TIDE algorithms, and drug sensitivity was predicted using GDSC database, with CETSA validating alpelisib-SPRED3 binding. Results SPRED3 was significantly upregulated in gastric cancer tissues and cells, demonstrating diagnostic value (AUC = 0.794) and a significant association with poor prognosis. Knockdown of SPRED3 inhibited cell proliferation, migration, and invasion, and suppressed the MAPK and NF-κB pathways. SPRED3 expression correlated positively with M2 macrophage infiltration and immune checkpoints (PD-L1, CTLA-4), and negatively with CD8+ T cells and activated NK cells. High SPRED3 expression was associated with elevated tumor immune dysfunction and exclusion scores, indicating immune exclusion and poor immunotherapy response, whereas low SPRED3 expression predicted increased sensitivity to alpelisib. Discussion Our results indicate that SPRED3 serves as a prognostic and immunological biomarker in gastric cancer. Conceptually, this study introduces SPRED3 as a previously unrecognized regulator in gastric cancer pathogenesis and immunity.