Phosphatase of regenerating liver-3 as a convergent therapeutic target for lymph node metastasis in esophageal squamous cell carcinoma.
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.
Ooki
Akira
A
Department of Surgery, Kitasato University Hospital, Sagamihara, Kanagawa, Japan. gekaw@med.kitasato-u.ac.jp
Yamashita
Keishi
K
Kikuchi
Shiro
S
Sakuramoto
Shinichi
S
Katada
Natsuya
N
Watanabe
Masahiko
M
D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008207:Lymphatic Metastasis / Q000503:physiopathology*; D008875:Middle Aged; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology
C550529:1-(2-bromobenzyloxy)-4-bromo-2-benzylidene rhodanine; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D012236:Rhodanine; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases