CREB3L4 promotes angiogenesis and tumor progression in gastric cancer through regulating VEGFA expression.

Tumor angiogenesis is a key step in the progression of gastric cancer (GC) that delivers essential nutrients and oxygen to tumor cells and distant sites. The cyclic AMP responsive element-binding protein 3-like 4 (CREB3L4) is a transcription factor highly expressed in multiple human cancers. This study aimed to investigate the regulatory effects of CREB3L4 on GC progression and angiogenesis. CREB3L4 was overexpressed in GC tissues and cell lines, and was positively correlated with advanced tumor stage and poor survival in GC patients. The upregulation of CREB3L4 in GC cells increased cell viability, promoted cell proliferation, reduced apoptosis, enhanced cell migration and invasion, and induced the formation of tubule-like endothelial structures, whereas CREB3L4 knockdown impeded tumor cell growth, attenuated cell motility, and prevented human umbilical vein endothelial cells from forming tubule-like structures. In addition, mice inoculated with CREB3L4-deficient GC cells showed significantly suppressed tumor growth compared to the group harboring wild-type tumors. Further analysis revealed that CREB3L4 expression was positively correlated with the level of vascular endothelial growth factor A (VEGFA) in gastric tumors. CREB3L4 regulated the transcription activity of VEGFA by binding to its promoter. The downregulation of VEGFA eliminated CREB3L4-induced GC cell growth and movement, and the formation of endothelial structures; while VEGFA upregulation greatly induced the growth and movement of GC cells with CREB3L4 deficiency. In conclusion, CREB3L4 promoted gastric tumor progression and endothelial angiogenesis by transcriptionally activating the VEGFA promoter, suggesting that therapeutic potential of the CREB3L4/VEGFA axis in GC treatment.