title: Mda-9/syntenin is expressed in uveal melanoma and correlates with metastatic progression.
abstract: Uveal melanoma is an aggressive cancer that metastasizes to the liver in about half of the patients, with a high lethality rate. Identification of patients at high risk of metastases may provide indication for a frequent follow-up for early detection of metastases and treatment. The analysis of the gene expression profiles of primary human uveal melanomas showed high expression of SDCBP gene (encoding for syndecan-binding protein-1 or mda-9/syntenin), which appeared higher in patients with recurrence, whereas expression of syndecans was lower and unrelated to progression. Moreover, we found that high expression of SDCBP gene was related to metastatic progression in two additional independent datasets of uveal melanoma patients. More importantly, immunohistochemistry showed that high expression of mda-9/syntenin protein in primary tumors was significantly related to metastatic recurrence in our cohort of patients. Mda-9/syntenin expression was confirmed by RT-PCR, immunofluorescence and immunohistochemistry in cultured uveal melanoma cells or primary tumors. Interestingly, mda-9/syntenin showed both cytoplasmic and nuclear localization in cell lines and in a fraction of patients, suggesting its possible involvement in nuclear functions. A pseudo-metastatic model of uveal melanoma to the liver was developed in NOD/SCID/IL2Rγ null mice and the study of mda-9/syntenin expression in primary and metastatic lesions revealed higher mda-9/syntenin in metastases. The inhibition of SDCBP expression by siRNA impaired the ability of uveal melanoma cells to migrate in a wound-healing assay. Moreover, silencing of SDCBP in mda-9/syntenin-high uveal melanoma cells inhibited the hepatocyte growth factor (HGF)-triggered invasion of matrigel membranes and inhibited the activation of FAK, AKT and Src. Conversely syntenin overexpression in mda-9/syntenin-low uveal melanoma cells mediated opposite effects. These results suggest that mda-9/syntenin is involved in uveal melanoma progression and that it warrants further investigation as a candidate molecular marker of metastases and a potential therapeutic target.
authors.affiliation: Immunological Therapy Laboratory, National Cancer Research Institute, University Hospital San Martino, Genoa, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gangemi
authors.forename: Valentina
authors.initials: V
authors.lastname: Mirisola
authors.forename: Gaia
authors.initials: G
authors.lastname: Barisione
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.forename: Antonella
authors.initials: A
authors.lastname: Brizzolara
authors.forename: Francesco
authors.initials: F
authors.lastname: Lanza
authors.forename: Carlo
authors.initials: C
authors.lastname: Mosci
authors.forename: Sandra
authors.initials: S
authors.lastname: Salvi
authors.forename: Marina
authors.initials: M
authors.lastname: Gualco
authors.forename: Mauro
authors.initials: M
authors.lastname: Truini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Angelini
authors.forename: Simona
authors.initials: S
authors.lastname: Boccardo
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.forename: Irma
authors.initials: I
authors.lastname: Airoldi
authors.forename: Paola
authors.initials: P
authors.lastname: Queirolo
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
mesh_terms: D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D053676:Syntenins / Q000235:genetics* / Q000378:metabolism; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000098943:Uveal Melanoma
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; C109621:SDCBP protein, human; D053676:Syntenins; D017228:Hepatocyte Growth Factor