High PTP4A3 Phosphatase Expression Correlates with Metastatic Risk in Uveal Melanoma Patients

Abstract

A high percentage of uveal melanoma patients develop metastatic tumors predominantly in the liver. We studied the molecular profiles derived from gene expression microarrays and comparative genomic hybridization microarrays, to identify genes associated with metastasis in this aggressive cancer. We compared 28 uveal melanomas from patients who developed liver metastases within three years of enucleation with 35 tumors from patients without metastases or who developed metastases more than 3 years after enucleation. Protein tyrosine phosphatase type IV A member 3 (PTP4A3/PRL3), was identified as a strong predictor of metastasis occurrence. We demonstrated that the differential expression of this gene, which maps to 8q24.3, was not merely a consequence of 8q chromosome overrepresentation. PTP4A3 overexpression in uveal melanoma cell lines significantly increased cell migration and invasiveness in vivo, suggesting a direct role for this protein in metastasis. Our findings suggest that PTP4A3 or its cellular substrates could constitute attractive therapeutic targets to treat metastatic uveal melanomas. Cancer Res; 71(3); 666-74. Ó2010 AACR.

Molecular Pathology of Uveal Melanoma

“…139 The BAP1 gene encodes a deubiquitinating enzyme that binds to BRCA1 and BARD1 to form a tumour suppressor heterodimeric complex. 140 It is mapped to chromosome 3p21.31-p21.2, a region previously noted by Trolet et al 129 to be deleted in UM. BAP1 is implicated in other cancers, which include mesothelioma, lung-, breast-and renal cell carcinomas.…”

Differential Expression of Fourteen Proteins between Uveal Melanoma from Patients Who Subsequently Developed Distant Metastases versus Those Who Did Not

“…Gene expression profiling studies have revealed that primary uveal melanoma clusters into two different classes; class 1 tumors are associated with a good prognosis and class 2 tumors with a high metastatic risk. [8][9][10] These studies also provide a number of potential genetic markers, such as PTP4A3, 11 which may have the capability to predict the progression and metastasis of uveal melanoma. It has also been shown that deletions and loss of heterozygosity of chromosome 3 correlate with an increased risk of metastasis.…”

Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells

“…The first PRL associated with cancer metastasis was PRL-3 (PTP4A3), which was found to be consistently expressed at high levels in all 18 human colorectal cancer (CRC) liver metastases examined, but at lower levels in the corresponding primary tumors and normal epithelium (2). In a recent study analyzing global gene expression patterns, PRL-3 was again identified as the most significant predictor of liver metastatic recurrence in uveal melanoma patients (3). These reports suggest a key role for PRL-3 in cancer metastasis.…”