Cripto-1 (CR-1) is a member of the epidermal growth factor-Cripto-1/FRL1/Cryptic gene family that plays a key role in thevarious malignant cancers. However, the role of CR-1 in prostate carcinoma (PCa) remains limited. The expression of CR-1was down-regulated by small interfering RNA (siRNA). Western blot measured the expression levels of CR-1 and somerelated proteins. We performed Cell Counting Kit-8, 5-ethynyl-2-deoxyuridine (EdU) incorporation assay and flowcytometry to detect the cellular proliferation and cycle. The transwell assay was used to observe cellular migration andinvasion. The ability of angiogenesis was evaluated by tube formation assay. Our results showed that CR-1 knockdownmarkedly inhibited cell proliferation and induced cycle arrest in G1 phase, as p21 and p27 were up-regulated, whereascyclin D1 and cyclin E1 were diminished. Moreover, silencing of CR-1 dramatically inhibited cell migration and invasion,repressed matrix metalloproteinases, and disturbed epithelial-mesenchymal transition. CR-1 siRNA suppressed the secretedlevel of vascular endothelial growth factor, and reduced protein level of Vascular endothelial growth factor receptor 2. Wefurther found that decreased CR-1 expression inhibited FAK/Src/PI3K and Wnt/b-catenin signalling in PCa cells. Theseresults suggested CR-1 might be served as an effective therapeutic target in PCa.