Differential Expression of Tissue Inhibitor of Matrix-metalloproteinases 3 in Uveal Melanoma

Abstract

Abstract: : Purpose: The tissue inhibitor of matrix-metalloproteinases 3 (TIMP-3) is a factor with inhibitory effect upon matrix metalloproteinases (MMPs) like the other TIMPs. Among TIMPs only TIMP-3 is stored in the extracellular matrix (ECM) mainly by heparan sulphate-proteoglycans. The diverse possibilities for interactions between MMPs and TIMPs in terms of matrix degradation and MMP-activation has been only partially investigated in uveal melanoma and some reports found an association between MMPs and patient survival. Recently TIMP-3 is thought to be involved even in apoptosis. In the present study the expression of TIMP-3 and its association with genetical and histopathological features was investigated. Methods: Twenty primary uveal melanomas were collected immediately after surgery and RNA was isolated for microarray analysis (Affymetrix, HG-U95Av2). Using a Wilcoxon rank test on the basis of chromosome 3 status (assessed with microsatellite analysis) several differentially expressed genes were identified. Immunohistochemistry, including antigen retrieval, was used to localise TIMP-3 (Acris, monoclonal antibody 136-13H4) in paraffin sections of enucleated human eyes containing the same primary tumors investigated by microarray analysis. Results: The mRNA expression level of TIMP-3 was associated with the chromosome 3 status. Tumors with monosomy 3 showed very low levels of expression whereas tumors with disomy 3 were expressing high levels of TIMP-3 (p=0.002). These results could be tendencially confirmed by the immunohistochemical detection of TIMP-3. There was no further association between TIMP-3 expression and histopathological or genetical features (tumor location, histological type, vascular patterns, aberrations in chromosome 6 and 8). Conclusions: TIMP-3 is differentially expressed among uveal melanomas. The absence of TIMP-3 in tumors with monosomy 3, which are aggressive and highly metastatic tumors, may indicates a possible role of TIMP-3 in the dissemination of uveal melanoma.

Keywords: tumors • uvea • choroid