Impact of PLA2G2A rs11573156 C > G Variant on Phospholipase Expression and Metastatic Behavior in Prostate Cancer

Prostate cancer (PCa) is a major global health concern and a leading cause of cancer-related deaths in men. Despite available treatments, PCa frequently recurs and exhibits high metastatic potential. One key factor in its malignancy is PLA2G2A, a secretory phospholipase A2 enzyme with strong inflammatory properties. Elevated PLA2G2A levels in the bloodstream have been linked to tumor grade, potentially due to the rs11573156 C > G polymorphism in the gene's 5' untranslated region (5'UTR). Previously, we demonstrated that individuals carrying the G allele have a 2.5-fold lower risk of developing metastatic PCa compared to those with the C allele. To further investigate the functional impact of this polymorphism, we employed CRISPR-Cas9 base editing to convert the GC genotype of metastatic PC-3 prostate cancer cells into the homozygous GG genotype. Our findings indicate that the G allele enhances PLA2G2A expression while downregulating genes associated with epithelial-to-mesenchymal transition (EMT), an effect reversed upon siRNA-mediated PLA2G2A silencing. Furthermore, this genetic alteration impaired the migratory capacity of PC-3 cells following interferon-γ (IFN-γ) priming, simulating an inflammatory tumor microenvironment. Notably, siRNA-induced downregulation of PLA2G2A reversed the anti-migratory effects associated with the GG genotype. Our results suggest that increased PLA2G2A expression, driven by the G allele, negatively affects cell proliferation, EMT, and metastatic properties, underscoring its potential anti-tumor role in PCa.