SIRT7-mediated desuccinylation of PRMT5 activates the ERK1/2-VEGF-C axis to promote lymphangiogenesis in gastric cancer

Lymphangiogenesis plays a significant role in tumor metastasis, making it a critical target for cancer therapies. PRMT5, an oncogene involved in various cellular processes, and SIRT7, a desuccinylase, regulate this process in gastric cancer (GC) through complex signaling pathways. However, the specific role of PRMT5 in tumor-induced lymphangiogenesis remains largely unexplored. This study investigates the role of SIRT7 in modulating PRMT5 expression and its impact on lymphangiogenesis through the ERK1/2 signaling pathway in GC. All functional assays were performed using human lymphatic endothelial cells (HLECs). HLECs were subjected to PRMT5 and SIRT7 knockdown or overexpression via lentiviral transfection. Cell proliferation was evaluated by CCK-8 assay, tube formation was assessed using Matrigel assays, and protein expression was detected by Western blotting. VEGF-C secretion was measured by ELISA, and Co-immunoprecipitation was performed to examine the interaction between SIRT7 and PRMT5. The ERK1/2 signaling pathway was analyzed to elucidate downstream mechanisms. PRMT5 knockdown inhibited lymphangiogenesis and reduced VEGF-C expression, while SIRT7 suppression increased PRMT5 levels, enhancing endothelial cell proliferation and tube formation. Western blotting showed that PRMT5 activates the ERK1/2 pathway, which is essential for VEGF-C regulation. Co-immunoprecipitation further confirmed a direct interaction between SIRT7 and PRMT5, supporting the regulatory link between these proteins. We identify the SIRT7/PRMT5/ERK1/2/VEGF-C axis as a novel and key regulator of lymphangiogenesis in GC, with significant potential therapeutic implications.