title: Melanoma Cell Adhesion and Migration Is Modulated by the Uronyl 2-O Sulfotransferase.
abstract: Although the vast majority of melanomas are characterized by a high metastatic potential, if detected early, melanoma can have a good prognostic outcome. However, once metastasised, the prognosis is bleak. We showed previously that uronyl-2-O sulfotransferase (Ust) and 2-O sulfation of chondroitin/dermatan sulfate (CS/DS) are involved in cell migration. To demonstrate an impact of 2-O sulfation in metastasis we knocked-down Ust in mouse melanoma cells. This significantly reduced the amount of Ust protein and enzyme activity. Furthermore, in vitro cell motility and adhesion were significantly reduced correlating with the decrease of cellular Ust protein. Single cell migration of B16VshUst(16) cells showed a decreased cell movement phenotype. The adhesion of B16V cells to fibronectin depended on α5β1 but not αvβ3 integrin. Inhibition of glycosaminoglycan sulfation or blocking fibroblast growth factor receptor (FgfR) reduced α5 integrin in B16V cell lines. Interestingly, FgfR1 expression and activation was reduced in Ust knock-down cells. In vivo, pulmonary metastasis of B16VshUst cells was prevented due to a reduction of α5 integrin. As a proof of concept UST knock-down in human melanoma cells also showed a reduction in ITGa5 and adhesion. This is the first study showing that Ust, and consequently 2-O sulfation of the low affinity receptor for FgfR CS/DS, reduces Itga5 and leads to an impaired adhesion and migration of melanoma cells.
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.|Centre for Internal Medicine, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Katerina
authors.initials: K
authors.lastname: Nikolovska
authors.affiliation: Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors.forename: Dorothe
authors.initials: D
authors.lastname: Spillmann
authors.affiliation: Comprehensive Cancer Center Münster, University Hospital Münster, Münster, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Haier
authors.affiliation: Department of Surgical and Molecular Pathology, National Institute of Oncology, Budapest, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ladányi
authors.affiliation: Centre for Internal Medicine, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Stock
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.|Centre for Internal Medicine, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Daniela G
authors.initials: DG
authors.lastname: Seidler
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020868:Gene Silencing; D039482:Integrin alpha5 / Q000235:genetics; D008175:Lung Neoplasms / Q000556:secondary*; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*
chemical_list: D039482:Integrin alpha5; D051496:Receptor, Fibroblast Growth Factor, Type 1; D015238:Sulfotransferases; C000606136:uronyl 2-O-sulfotransferase, mouse