PAFAH1B3 promotes gastric cancer progression by enhancing E2F8-mediated transcriptional activation of VEGFA expression.

Gastric cancer has remained as a top ranked human malignancy showing both high morbidity and mortality, especially in Asian countries. Recent advances have revealed actionable targets for clinical gastric cancer therapy, including epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor receptor (VEGFR), thus calling for further investigation of potential therapeutic targets. Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3) functions to remove the acetyl group from platelet-activating factor and is implicated in multiple diseases including cancer. However, the exact roles and underlying mechanisms of PAFAH1B3 in gastric cancer are incompletely investigated. By combining bioinformatic and gastric cancer tissue analyses, we confirmed that PAFAH1B3 was upregulated in gastric cancer and reversely correlated with patient prognosis showing significant association with tumor stages and metastasis. PAFAH1B3 knockdown rendered suppressed proliferation and migration, but enhanced apoptosis of gastric cancer cells. Transcriptomic profiling of control and PAFAH1B3 knockdown cells revealed VEGFA as a downstream effector, the overexpression of which effectively rescued defects imposed by PAFAH1B3 knockdown. Further investigation showed that PAFAH1B3 coordinated with the transcription factor E2F8 to promote VEGFA transcription. Importantly, in xenograft animal models, PAFAH1B3 overexpression significantly enhanced tumorigenesis, while VEGFA knockdown effectively suppressed gastric cancer xenograft growth. Therefore, our findings suggest that the PAFAH1B3/E2F8/VEGFA pathway plays an important role in gastric cancer progression, which can be targeted to design novel therapeutic strategies against gastric cancer.