Phosphatase of regenerating liver-3 (PRL-3) has received attention as a molecule associated with metastasis in various tumor types, including gastric cancer. However, its clinical utility as a biomarker remains unclear in primary gastric cancer. The present study included 173 patients with primary gastric cancer who underwent gastrectomy with regional lymphadenectomy at the Kitasato University Hospital. All patients were informative for the well-characterized clinicopathological variables, including patient outcome. We assessed the potential as a clinically applicable biomarker using immunohistochemistry. PRL-3 overexpression was detected in 78 (45%) of 173 primary tumor tissues and was an independent predictor of lymph node metastasis on multivariate logistic regression analysis (odds ratio=9.32; P<0.0001). PRL-3 overexpression in primary tumor had significant prognostic implication (P=0.0009) and was also an independent prognostic factor (hazard ratio=4.39; P=0.006) in the histologically node-negative patients after curative resection, but not in the histologically node-positive patients. Moreover, in advanced gastric cancer with stage I disease, PRL-3 overexpression inversely affected patient outcome (P=0.02) and showed a characteristic of stage II disease from a prognostic point of view. We demonstrated for the first time that PRL-3 expression in primary tumor could predict the outcome of patients with histologically node-negative gastric cancer. We propose that PRL-3 expression can have a clinical potential as a prognostic biomarker that may facilitate the development of adjuvant chemotherapy for advanced gastric cancer with stage I disease.

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