[Frontiers in Bioscience 14, 2504-2513, January 1, 2009]

Cathepsin S and its inhibitor cystatin C: imbalance in uveal melanoma

Luminita Paraoan1, Donna Gray1, Paul Hiscott1, 2, Marta Garcia-Finana3, Brian Lane3, Bertil Damato4, Ian Grierson1

1Unit of Ophthalmology, School of Clinical Science, University of Liverpool, Liverpool, UK, 2Department of Pathology, Royal Liverpool University Hospital, Liverpool, UK, 3Centre for Medical Statistics and Health Evaluation, University of Liverpool, Liverpool, UK, 4Ocular Oncology Centre, St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods
3.1. Tumor specimens
3.2. Western immunoblotting analysis
3.3. Immunohistochemical analysis
3.4. Statistical analysis
4. Results
4.1. Expression levels of cathepsin S and cystatin C in primary uveal melanoma
4.2. Statistical analysis of cathepsin S and cystatin C differential expression
4.3. Immunostaining of cathepsin S and cystatin C in primary uveal melanoma tumors
5. Discussion
6. Acknowledgment
7. References

1. ABSTRACT

The present study aimed to investigate, as a follow-up of microarray profiling, the expression of the lysosomal cysteine protease cathepsin S and that of its endogenous inhibitor cystatin C in the most common primary intraocular tumor in adults, uveal melanoma. The expression pattern unveiled was characterized by a relative increase in the active form of the elastolytic and collagenolytic cathepsin S that was not counterbalanced by the expression of its strongest endogenous inhibitor cystatin C in the aggressive, highly metastatic uveal melanomas. The study provides evidence for a novel correlation between a specific cysteine protease activity and the strongest predictive factor for metastatic behavior in primary uveal melanoma and documents the first investigation of both a specific protease activity and its endogenous inhibitor in uveal melanoma. The results indicate that the shift in the balance between cathepsin S and cystatin C may be part of deregulated proteolytic pathways contributing to the invasive phenotype of uveal melanoma.