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

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 5 0.0014, relative risk 515.20). 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, anchorageindependent 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.

Phosphatase of regenerating liver‐3 promotes migration and invasion by upregulating matrix metalloproteinases‐7 in human colorectal cancer cells

“…35 In this study, it was confirmed using U-0126 (an ERK inhibitor) and LY-294002 (a PI3K inhibitor) that PRL-3 upregulated the expression of MMP-7 through these oncogenic signaling pathways. The results suggest that the PI3K/AKT and ERK pathways are involved in the induction of MMP-7 by PRL-3.…”

Genomic and epigenetic profiles of gastric cancer: Potential diagnostic and therapeutic applications

“…66 The molecule was initially believed to be involved in distant metastasis of colorectal cancer, but subsequent research has revealed that PRL-3 plays a causative role in lymph node metastasis in diverse cancers, including gastric cancers. 67-77 PRL-3 is a tyrosine phosphatase that is needed for cancer invasion, motility, and metastasis [77][78][79] as well as angiogenesis, 80 which may be regulated by dephosphorylation of several molecules, such as integrins, 81,82 Ezrin, 83 or cadherin. 84 We recently demonstrated that a PRL-3 inhibitor (1,4-bromo-2-benzylidene rhodamine) dramatically suppressed the metastatic capacity in cell lines with PRL-3 overexpression, irrespective of the DNA amplifi cation status in esophageal cancer.…”

Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer

“…Immunohistochemistry was carried out using the anti-HOPX polyclonal antibody (dilution of 1:100), as described previously (Ooki et al, 2009). As HOPX immunoreactive scoring algorithms had not been optimized and standardized, the expression status was assessed using a German scoring system (Supplementary Table 5) (Remmele and Stegner, 1987).…”

“…Anchorage-independent cell growth assay was carried out as described previously (Ooki et al, 2009). Cells were fed weekly by overlying fresh soft-agar solution containing G418, and colonies were photographed after 2 weeks of incubation.…”

“…The invasion assay was performed in the 24-well BD BioCoat Matrigel Invasion Chamber (BD Biosciences Discovery Labware, Bedford, MA, USA), as described previously (Ooki et al, 2009). After incubation for 22 h, membrane of the upper chamber was fixed and stained by Diff-Quik reagent (Sysmex, Kobe, Japan).…”