In this study, through integrative analysis of the cis-regulatory elements and public datasets of chromatin immunoprecipitation (ChIP) and microarray, we identified microRNA-558 (miR-558) and SMAD family member 4 (Smad4) as crucial transcriptional regulators of HPSE expression in gastric cancer, with their adjacent target sites within the HPSE promoter. Here, SMAD4 is linked to gastric cancer.