Abstract
Phosphatase of regenerating liver-3 (PRL-3) has been reported to be associated with colon and gastric cancer metastasis. However, the role and function of PRL-3 in human non-small cell lung cancer cells is unknown. Our studies showed that the expression of PRL-3mRNA and protein are higher in less invasive human lung adenocarcinoma cells than in highly invasive cell lines. Ectopic expression of PRL-3 reduced cell capacity for anchorage-dependent growth, anchorage-independent growth, migration, and invasion in vitro, as well as tumorigenesis in vivo. Conversely, catalytic (C104S) and prenylation-site (C170S) mutants enhanced cell invasion. Microarray profiling of PRL-3 transfectants revealed the pathways potentially involving PRL-3, including the epithelial-mesenchymal transition (EMT), extracellular matrix remodeling, and the WNT signaling pathway. Furthermore, we demonstrated that increased PRL-3 reduced Slug and enhanced E-cadherin gene expression through the AKT/GSK3β/β-catenin pathway. In conclusion, our data suggest that PRL-3 might play a tumor suppressor role in lung cancer, distinct from other cancers, by inhibiting EMT-related pathways.
Highlights
Non‐small‐cell lung cancer (NSCLC) is responsible for the most frequent cause of cancer‐related death [1,2,3]
The data revealed a correlation between Phosphatase of regenerating liver‐3 (PRL‐3) expression and cell invasive capability in NSCLCs
Previous studies have shown that PRL‐3 expression positively correlates with cancer progression, especially in colorectal cancer [21, 22]
Summary
Non‐small‐cell lung cancer (NSCLC) is responsible for the most frequent cause of cancer‐related death [1,2,3]. Metastasis is one of the major determinants leading to cancer progression and a complex and multi‐step process including enhanced cellular motility and extracellular matrix degradation [7]. Protein tyrosine phosphorylation is an important posttranslational modification regulating the intracellular signaling pathways that determine cellular physiologic and pathologic processes. Phosphatase of regenerating liver‐3 (PRL‐3), known as PTP4A3, is a PRL‐PTP identified as possessing a C‐terminal prenylation motif (CAAX box). This motif causes PRL‐3 to be posttranslationally modified by farnesyltransferase, and farnesylated PRL‐3 localizes to the plasma membrane and early endosomes. Inhibiting farnesylation leads to a localization shift of PRL‐3 into the nucleus to mediate its function. The catalytic site CX5R of PRL‐3 functions as a dual‐specificity phosphatase that is able to dephosphorylate tyrosine, serine, and threonine residues in some cases [9]
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