title: Increased levels of DUSP6 phosphatase stimulate tumourigenesis in a molecularly distinct melanoma subtype.
abstract: The mitogen-activated protein kinase (MAPK) pathway is important in melanoma. In this pathway, DUSP6 phosphatase negatively controls the activation of extracellular signal-regulated (ERK) kinase. Through comparison of melanoma signalling pathways between immortal mouse melanocytes and their tumourigenic derivatives, retrieved from mouse xenografts, we identified a molecularly distinct subtype of melanoma, characterized by reduced ERK activity and increased DUSP6 expression. Overexpression of DUSP6 enhanced anchorage-independent growth and invasive ability of immortal mouse melanocytes, suggesting that increased DUSP6 expression contributes to melanoma formation in the mouse xenografts. In contrast, reduced tumourigenicity was observed after DUSP6 overexpression in human melanoma cells. A minority of thick human primary melanomas had high DUSP6 expression and the same poor melanoma-specific survival as the majority of thick primaries with low DUSP6 levels. We have demonstrated that DUSP6 is important in melanoma and that it plays a different role in our distinct subtype of mouse melanoma compared with that in classic human melanoma.
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Weiling
authors.initials: W
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Song
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Ritchie
authors.forename: David W
authors.initials: DW
authors.lastname: Melton
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000201:enzymology / Q000473:pathology; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse