Fascin-1 (FSCN1) is an actin-bundling protein that induces cell membrane protrusions, increases cell motility,and is overexpressed in various human epithelial cancers, including esophageal squamous cell carcinoma (ESCC).We analyzed various protein-protein interactions (PPI) of differentially-expressed genes (DEGs), in fascinknockdown ESCC cells, to explore the role of fascin overexpression. The node-degree distributions indicated thesePPI sub-networks to be characterized as scale-free. Subcellular localization analysis revealed DEGs to interactwith other proteins directly or indirectly, distributed in multiple layers of extracellular membrane-cytoskeleton/cytoplasm-nucleus. The functional annotation map revealed hundreds of significant gene ontology (GO) terms,especially those associated with cytoskeleton organization of FSCN1. The Random Walk with Restart algorithmwas applied to identify the prioritizations of these DEGs when considering their relationship with FSCN1. Theseanalyses based on PPI network have greatly expanded our comprehension of the mRNA expression profilefollowing fascin knockdown to future examine the roles and mechanisms of fascin action.