Clinical significance of PRL-3 genomic amplification/expression profiles and preclinical study of PRL-3 inhibitor in human gastrointestinal cancers.

Abstract

3071 Background: PRL (phosphatase of regenerating liver) is a tyrosine phosphatase that dephosphorylates molecules involved in cancer invasion and metastasis and subsequently activates either PI3 kinase or Src pathway. PRL-3 was initially identified as a gene that is amplified in metastasis of colorectal cancer. We are thinking much of clinical potential of PRL-3 inhibitor as a molecular targeted therapy in GI cancer. Methods: Immunohistochemistry and genomic status were assessed for PRL-3 in esophageal squamous cell carcinoma (ESCC)(n=88), gastric adenocarcinoma (n=173), and colorectal adenocarcinoma (n=107).RNA interference was used to determine its specific functional roles in GI cancers. Preclinical study using PRL-3 inhibitors (1-4-bromo-2-benzylidene rhodanine) was performed in 4 ESCC and 4 gastric cancer cell lines that were intensely expressed for PRL-3, or TE5 which showed basal level expression. Results: (1) PRL-3 expression is associated with lymph node metastasis in primary ESCC (p=0.0012), gastric adenocarcinoma (p<0.0001), and colorectal carcinoma (p<0.0001). In the primary tumors with lymph node metastasis, its expression was recognized in 96, 80, 86%, respectively. (2) If restricted to patients with PRL-3 expression, genomic amplification was found exclusively in stage IV ESCC (30%), and stage III/IV gastric cancer (40%). In colorectal cancer, PRL-3 genomic amplification is found in 35% of stage III/IV, but only in 10% of stage II (p=0.002). (3) PRL-3 RNA interference robustly suppressed metastatic cancer phenotypes. (4) PRL-3 inhibitor suppressed phenotypes as well in a dose dependent manner (0, 1, 10, and 50 mM). Interestingly, 10 mM of the inhibitor could not suppress muscle cell (C2C12) that endogenously express PRL-3, but 50 mM suppressed it. Conclusions: PRL-3 inhibitor has a great clinical potential to suppress tumors with metastatic ability, that was represented by lymph node metastasis or recurrent disease of GI cancers.