PLA2G2A rs11573156 C>G polimorfizmin fosfolipaz aktivitesi ve prostat kanseri gelişimindeki rolü

Prostate cancer (PCa) is one of the most common health problems and cause of cancer-related mortality among men worldwide. Despite the existence of many treatment options, PCa is a recurrent disease with highly metastatic characteristics, often resistant to chemotherapy. The phospholipase A2 (PLA2) enzyme promotes the hydrolysis of the fatty acid acyl ester bond of phosphoglycerides, leading to the release of free acids and formation of lysophospholipids. Secretory PLA2 group II (sPLA2G2A) is one of the secreted forms in the PLA2 family members, which acts as an extracellular enzyme. PLA2G2A is responsible for the biosynthesis of prostaglandins and leukotrienes, which have potent inflammatory properties. Inflammatory responses have important roles at different stages of tumor development. PLA2G2A was associated with various types of cancer and malignancies, including prostate cancer. Previous studies have shown that elevated serum levels of PLA2G2A in patients with prostate cancer was in association with the tumor grade. This elevation in serum levels of PLA2G2A may in part be due to an SNP on the 5'UTR region (rs11573156 C>G polymorphism) on the gene. A previous study of our group suggested that patients carrying the G allele on the 5'UTR region of the PLA2G2A gene were 2.5 times less susceptible to development of metastatic PCa compared with those carrying the C allele. The aim of this thesis was to model the 5'UTR (rs11573156 C>G) polymorphism of PLA2G2A in metastatic PC-3 prostate cancer cell lines by editing GC genotype to the homozygous GG genotype using the CRISPR/Cas9 technology. Following gene editing, functional analysis of the PC-3 prostate cancer cell line with GG genotype was performed. This study is the first to investigate the effect of PLA2G2A rs11573156 SNP in PLA2G2A expression as well as proliferation and cell cycle regulation in PCa. Our findings demonstrate for the first time in literature that the homozygous G allele elevates the PLA2G2A expression, decreases the proliferation rate of PC-3 cells by attenuating the transition from G1 phase to S phase in response to hydrogen peroxide and interferon-γ that mimics the inflammatory tumor microenvironment.