Abstract:Background and Aims Krüppel-like factor 5 (KLF5) and endothelial cell-specific molecule 1 (ESM1) are closely associated with tumor progression. However, whether KLF5 promotes gastric cancer progression through transcriptional regulation of ESM1 remains unclear. This study investigated the regulatory relationship between KLF5 and ESM1 and their roles in GC progression.Methods Thirty paired gastric cancer and adjacent normal tissues were collected. The expression of KLF5 and ESM1 was determined by qRT-PCR, Western blot and immunohistochemistry. The UALCAN and JASPAR databases were used to analyze gene expression and predict potential binding sites. Dual-luciferase reporter assays and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were performed to verify the transcriptional regulation of ESM1 by KLF5. Functional assays including colony formation, wound-healing and Transwell assays were conducted to evaluate cell proliferation, migration and invasion. A nude mouse xenograft model was established to assess the in vivo effects.Results ESM1 expression was significantly elevated in gastric cancer tissues and cell lines compared with corresponding controls (all P<0.05). KLF5 was also highly expressed in GC tissues. Bioinformatics analysis predicted a KLF5-binding site within the ESM1 promoter region. Dual-luciferase reporter and ChIP-qPCR assays confirmed that KLF5 directly bound to the ESM1 promoter and transcriptionally activated ESM1 expression. Knockdown of either KLF5 or ESM1 significantly inhibited the proliferation, migration and invasion of AGS and HGC-27 cells (all P<0.05). ESM1 overexpression markedly reversed the suppressive effects induced by KLF5 silencing (all P<0.05). In vivo experiments further demonstrated that KLF5 knockdown inhibited xenograft tumor growth, whereas ESM1 overexpression partially rescued tumor growth.Conclusion KLF5 promotes gastric cancer cell proliferation, migration, invasion, and tumorigenesis by directly transcriptionally activating ESM1. The KLF5-ESM1 regulatory axis may serve as a promising molecular target for the diagnosis and treatment of gastric cancer.