title: Tissue inhibitor of metalloproteinase-3 (TIMP3) expression decreases during melanoma progression and inhibits melanoma cell migration.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Collectively, our data suggests that TIMP3 functions as a tumour suppressor in melanoma and negatively regulates several aspects of the metastatic cascade.
authors: Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: a.mooppilmadhamdas@erasmusmc.nl.
authors: Asha M
authors: AM
authors: Das
authors: Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Michiel
authors: M
authors: Bolkestein
authors: Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Thom
authors: T
authors: van der Klok
authors: Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Charlotte M C
authors: CM
authors: Oude Ophuis
authors: Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Cindy E
authors: CE
authors: Vermeulen
authors: Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Joost A P
authors: JA
authors: Rens
authors: Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Winand N M
authors: WN
authors: Dinjens
authors: Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Peggy N
authors: PN
authors: Atmodimedjo
authors: Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Cornelis
authors: C
authors: Verhoef
authors: Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Senada
authors: S
authors: Koljenović
authors: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Ron
authors: R
authors: Smits
authors: Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Timo L M
authors: TL
authors: Ten Hagen
authors: Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands; Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Electronic address: alexander.eggermont@gustaveroussy.fr.
authors: Alexander M M
authors: AM
authors: Eggermont
mesh_terms: D000328:Adult; D000368:Aged; D002465:Cell Movement / Q000502:physiology; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D012878:Skin Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3
keywords: Melanoma; Metastasis; Migration; TIMP3