PRL-3 increases the aggressive phenotype of prostate cancer cells in vitro and its expression correlates with high-grade prostate tumors in patients

The increased expression of phosphatase of regenerating liver-3 (PRL-3) has been shown to be associated with the aggressive and metastatic phenotype of different solid tumors. However, it is not known whether PRL-3 plays a similar role in the progression of prostate cancer (PCa). In this study, immunoblot analysis of androgen receptor (AR)-positive PCa lines (LNCaP and LNCaP-SF) revealed the constitutive cytoplasmic expression of PRL-3, and stimulation with R1881 (AR agonist) rapidly increased the nuclear translocation of PRL-3. The AR-negative cell lines exhibited negligible PRL-3 expression, and the ectopic overexpression of PRL-3 increased both the proliferative and invasive potential of PC3 and DU145 cells. In addition, we measured PRL-3 protein expression in human prostate tumor sections. A high-density prostate tumor microarray (TMA) was immunostained to assess whether PRL-3 expression and its subcellular localization (cytoplasmic and nuclear levels) is associated with the Gleason score (GS), Gleason grade (GG) and tumor stage (T-stage). Digital image analysis (DIA) revealed that PRL-3 expression was significantly higher in the malignant cores, as compared to the non-malignant areas. Increases in both total and nuclear PRL-3 levels were also associated with a higher GS and GG. Metastatic tumors (T4-stage) had lower cytoplasmic, but higher nuclear PRL-3 levels. Furthermore, the nuclear/cytoplasmic ratio for PRL-3 in the tumors graded as GS7 could effectively distinguish between indolent (3+4) and aggressive (4+3) disease. Thus, our experiments using PCa lines suggested that PRL-3 is an AR-regulated gene and its androgen-induced nuclear localization may increase the aggressive behavior of PCa cells. Furthermore, the digital analysis of immunostained tumor sections suggested that PRL-3 may be an effective biomarker of high-grade PCa, and its nuclear/cytoplasmic ratio may be used to distinguish between indolent vs. aggressive tumors.