Proteomic profiling identifies an oncogene ITGA2 and its downstream targets in gastric cancer.

[PURPOSE] Gastric cancer is a leading cause of cancer-related mortality worldwide, with metastasis being the primary cause of death. Exosomes secreted by tumor cells are key mediators of intercellular communication and can prepare distant sites for metastasis by altering the local microenvironment. We hypothesized that exosomes released by gastric cancer cells deliver cargo that regulates specific proteins in recipient gastric cancer cells, thereby enhancing tumor progression and metastatic potential.

[METHODS] Human gastric cancer cell lines were treated with exosomes isolated from the conditioned medium of other gastric cancer cells. Differential proteomic analysis was performed to identify proteins significantly altered by exosome treatment. ITGA2 expression was validated in exosome-treated cells and in clinical gastric cancer tissues versus adjacent normal tissues using RT-qPCR and western blotting. The functional role of ITGA2 was assessed by siRNA-mediated knockdown, followed by MTT proliferation assays and fluorometric transwell assays for migration and invasion. A second proteomic analysis was conducted on ITGA2-knockdown versus control cells to identify downstream targets and affected pathways.

[RESULTS] Exosome treatment significantly upregulated ITGA2 expression in recipient gastric cancer cells. ITGA2 was also markedly overexpressed in human gastric cancer tissues compared with adjacent normal mucosa. Knockdown of ITGA2 significantly suppressed cell proliferation, migration, and invasion. Proteomic profiling of ITGA2-knockdown cells revealed numerous differentially expressed proteins enriched in pathways related to cell adhesion, motility, extracellular matrix organization, and intercellular signaling.

[CONCLUSION] Exosomes derived from gastric cancer cells induce ITGA2 overexpression in recipient tumor cells, where ITGA2 functions as an oncogene that promotes proliferation, migration, and invasion. The downstream targets of ITGA2 implicate multiple pro-tumorigenic signaling networks, suggesting that the exosomes-ITGA2 axis may represent a novel therapeutic target in gastric cancer progression and metastasis.