Overexpression of phosphatase of regenerating liver (PRL)-3 is associated with the progression of diverse human cancers. We show that the overexpression of PRL-3 protein is not directly associated with its transcript levels, indicating the existence of an underlying posttranscriptional regulation. The 5′ untranslanted region (UTR) of PRL-3 mRNA possesses triple GCCCAG motifs capable of suppressing mRNA translation through interaction with PolyC-RNA-binding protein 1 (PCBP1), which retards PRL-3 mRNA transcript incorporation into polyribosomes. Overexpression of PCBP1 inhibits PRL-3 expression and inactivates AKT, whereas knockdown of PCBP1 causes upregulation of PRL-3 protein levels, activation of AKT, and promotion of tumorigenesis. An inverse correlation between protein levels of PRL-3 and PCBP1 in human primary cancers supports the clinical relevance. ► PRL-3 protein is upregulated in diverse human cancers ► PCBP1 suppresses PRL-3 translation via the 5′ UTR of the PRL-3 mRNA ► PCBP1 and PRL-3 protein levels were inversely correlated in human cancers ► The axis of PCBP1→PRL-3→AKT pathway in cancer cell signaling