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.
Highlights
Uveal melanoma is the most common intraocular cancer in adults
We further investigated the role of PTP4A3 in the development of tumor metastases, by characterizing the migration and invasiveness of uveal melanoma cell lines overexpressing this gene
PTP4A3 is overexpressed in meta1 tumors We investigated whether protein levels were correlated with mRNA levels for PTP4A3 in uveal melanoma tumors, we performed immunodetection of this protein in sections from meta0 and meta1 tumors
Summary
Uveal melanoma is the most common intraocular cancer in adults. Up to 50% of patients develop metastases within a median of 36 months, with a median survival of 6 months after metastasis [1]. Several clinical and histopathological features have been correlated with survival, including patient age (>60), anterior location of the tumor, tumor cell histology, largest diameter of the tumor, mitotic activity, and chromosome 3 monosomy. The most frequent chromosomal imbalances in uveal melanoma are loss of chromosome 3 and gains of 8q and 6p [2]. Several gene expression profiling studies have identified two molecular classes strongly associated with metastatic risk [3,4,5]. The application of one recently described gene classifier [6] to our data set (Supplementary Fig. 1) separates two classes, but 21% of metastasizing tumors
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