Recent reports suggested that phosphatase of regenerating liver (PRL)-3 might be involved in colorectal carcinoma metastasis with an unknown mechanism.Here we demonstrated that PRL-3 expression was upregulated in human liver carcinoma compared with normal liver. PRL-3 was also highly expressed in metastatic melanoma B16-BL6 cells but not in its lowly metastatic parental cell line, B16 cells. B16 cells transfected with PRL-3 cDNA displayed morphological transformation from epithelial-like shape to fibroblast-like shape. PRL-3-overexpressed cells showed much higher migratory ability, which could be reversed by specific anti-sense oligodeoxynucleotide and the phosphatase inhibitors sodium orthovanadate or potassium bisperoxo oxovanadate V. Meanwhile, the expression of the catalytically inactive PRL-3 mutations (D72A or C104S) significantly reduced the cell migratory capability. In addition, PRL-3 transfectants demonstrated altered extracellular matrix adhesive property and up-regulated integrin-mediated cell spreading efficiency. Furthermore, we confirmed that PRL-3 could facilitate lung and liver metastasis of B16 cells in an experimental metastasis model in mice, consistent with accelerated proliferation and growth rate both in vitro and in vivo. Together, these observations provide convincing evidence that PRL-3 truly plays a causal role in tumor metastasis. Metastasis is the leading cause of death in cancer patients and involves a complex, multistep process including detachment of tumor cells from a primary cancer, invasion of surrounding tissue, entry into the circulatory system, reinvasion, and proliferation at a distant secondary site. 1,2 A wide variety of stimuli have been associated with the spread of tumor cells, including cytokines, hormones, growth factors, cell adhesion molecules, and extracellular components. Many of these stimuli transmit signals via a tyrosyl phosphorylation pathways that dictate whether a tumor cell will grow and divide, change shape, migrate, differentiate, or die. Protein tyrosine phosphorylation is a major posttranslational modification that cells use to regulate signal transduction. The homeostasis of tyrosine phosphorylation is controlled by protein tyrosine kinases (PTKases) that catalyze tyrosine phosphorylation, and protein tyrosine phosphatase (PTPases) that are responsible for dephosphorylation. PTKases, PTPases, and their corresponding substrates are integrated into elaborate signaltransducing networks. Deregulation of phosphorylation is known to result in neoplastic or nonneoplastic disease.
4Phosphatases are as important as the well-studied PTKases because phosphorylation is a dynamic and reversible process. 5 The PTPase superfamily can be divided into three major classes: tyrosine-specific and low-molecular weight phosphatases, which strictly dephosphorylate phosphotyrosine residues, and dual-specific phosphatases, which use protein substrates that contain phosphotyrosine, phosphoserine, and phosphothreonine. Tyrosine-specific PTPases can be further divided into two ...