Tissue inhibitor of metalloproteinase-3 (TIMP3) expression decreases during melanoma progression and inhibits melanoma cell migration

• Published in: European journal of cancer (1990) 2016-10, Vol.66, p.34-46
• Main Authors: Das, Asha M, Bolkestein, Michiel, van der Klok, Thom, Oude Ophuis, Charlotte M.C, Vermeulen, Cindy E, Rens, Joost A.P, Dinjens, Winand N.M, Atmodimedjo, Peggy N, Verhoef, Cornelis, Koljenović, Senada, Smits, Ron, ten Hagen, Timo L.M, Eggermont, Alexander M.M
• Format: Article
• Language: English
• Subjects: Adult; Aged; Cell Movement - physiology; Disease Progression; DNA Methylation; Female; Hematology, Oncology and Palliative Medicine; Humans; Kaplan-Meier Estimate; Male; Melanoma; Melanoma - metabolism; Melanoma - mortality; Melanoma - pathology; Metastasis; Middle Aged; Migration; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Skin Neoplasms - metabolism; Skin Neoplasms - mortality; Skin Neoplasms - pathology; TIMP3; Tissue Inhibitor of Metalloproteinase-3 - metabolism
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2016.06.020

Abstract Aims Malignant melanoma is the most aggressive form of skin cancer, and metastatic dissemination to regional and visceral sites is responsible for the majority of melanoma-related mortalities. In a recent study by our group, we observed reduced expression of tissue inhibitor of metalloproteinase-3 (TIMP3) in the majority of stage III melanoma samples studied. TIMP3 has been reported as a tumour suppressor in several human malignancies, with reduced expression correlating with poor clinical outcome. In this study, we investigated the changes in TIMP3 expression during melanoma progression. Patients and methods TIMP3 expression was analysed by immunohistochemistry in sequential archived tumour material from stage I/II, stage III and stage IV samples from melanoma patients (n = 33). Protein expression was investigated for associations with disease-free survival and overall survival. Methylation status of the gene promoter was determined using methylation-specific PCR. In vitro assays were used to investigate the functional consequences of TIMP3 expression on behavioural aspects of melanoma cells. Results We show that TIMP3 expression decreases with melanoma progression although no significant clinical associations were obtained. Analysis of the status of promoter methylation using methylation-specific PCR revealed it to be a low-frequency event in melanoma. Additionally, through gene modulation experiments in melanoma cell lines, we show that TIMP3 negatively regulates cell migration, invasion and anoikis resistance. Conclusions Collectively, our data suggests that TIMP3 functions as a tumour suppressor in melanoma and negatively regulates several aspects of the metastatic cascade.