PCYT2-Mediated Regulation of Phospholipid Metabolism Enhances Metastasis in Epithelial Ovarian Cancer via the AKT/mTOR and HIPPO Signaling Pathways

Abstract

Background: Phosphatidylethanolamine (PE) is a vital component of cell membranes, and alterations in its content serve as an indicator of cancer metastasis risk. Phosphoethanolamine cytidine transferase-2 (PCYT2), an enzyme responsible for PE synthesis, is pivotal in promoting tumor cell proliferation and invasion. Inhibiting PCYT2 expression has the potential to reduce the occurrence of ovarian cancer metastasis and thereby improve the management of ovarian cancer. Methods: Ovarian cancer primarily manifests in the perimenopausal period, coinciding with significant changes in lipid metabolism. To elucidate this relationship, we conducted non-targeted lipid metabolomics analyses on primary and matched metastatic tissues from ten patients with epithelial ovarian cancer. Lipid metabolism in vivo is intricately linked to the synthesis of lipid metabolic enzymes, which are governed by genetic regulation. To study the relationship between lipid metabolism and gene expression, we performed transcriptomic analyses on primary and matched metastatic tissues from eight patients with epithelial ovarian cancer. To validate the robustness of our findings, we performed PCR and Western-blot analyses on tissues from 20 patients with epithelial ovarian cancer. Results: Our results reveals elevated PCYT2 expression in metastatic ovarian cancer tissues and abnormal phospholipid metabolism. Correlation analyses reveals a strong positive correlation between PCYT2 and phospholipid metabolism. Notably, PCYT2 expression is significantly higher in metastatic tissues compared to primary tissues (p < 0.001). Additionally, our study identifies decreased expression of phosphatase and tensin homolog (PTEN) and yes-associated protein (YAP1), coupled with elevated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) expression in metastatic tissues (p < 0.05). Notably, we observed disparities in the expression of PCYT2 proteins, with higher PCYT2-β expression in metastatic lesions (p < 0.001). Moreover, a specific mRNA transcribed by ENST00000572995 exhibits high expression in metastatic lesions. Conclusions: Based on our findings, we propose that PCYT2-β may play a significant role in driving the metastasis of epithelial ovarian cancer.