Phosphatase of regenerating liver‐3 as a convergent therapeutic target for lymph node metastasis in esophageal squamous cell carcinoma

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Abstract
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.

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