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Phosphatase of regenerating liver-3 (PRL-3) is a molecule associated with metastasis in a diverse of cancers, which, however, remains largely unknown in esophageal squamous cell carcinoma (ESCC). We examined both the clinical significance of PRL-3 expression and its biological roles, and assessed possibilities as a therapeutic target in ESCC. PRL-3 expression was found in 78% (69 of 88) of the primary ESCC on immunohistochemistry; it was the strong independent predictor for lymph node metastasis (LNM) on a multivariate logistic regression model (p = 0.0014, relative risk =15.20). Additionally, gene amplification was found in 3 (7.9%) of the 38 primary tumors with PRL-3 overexpression by fluorescence in situ hybridization, but in none of the 19 tumors without it. PRL-3 small interfering RNA robustly repressed cell proliferation, anchorage-independent colony formation and invasion and augmented 5-FU-induced apoptosis in all the tested ESCC cell lines with PRL-3 overexpression, irrespective of its gene amplification status. PRL-3 inhibitor (1-4-bromo-2-benzylidene rhodanine) also suppressed such metastatic properties in the cell lines with PRL-3 overexpression, but not with its low expression. Inverse effects were observed by PRL-3 forced expression. Collectively, PRL-3 overexpression is a frequent event associated with LNM and plays a causative role in promoting cancer progression. Moreover, the expression status may be a landmark to select patients with benefit from PRL-3-targeted therapy. Thus, PRL-3 could be a convergent therapeutic target against ESCC with LNM.