title: CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis.
abstract: Ewing sarcoma (EWS) is an aggressive bone tumor of uncertain cellular origin. CD99 is a membrane protein that is expressed in most cases of EWS, although its function in the disease is unknown. Here we have shown that endogenous CD99 expression modulates EWS tumor differentiation and malignancy. We determined that knocking down CD99 expression in human EWS cell lines reduced their ability to form tumors and bone metastases when xenografted into immunodeficient mice and diminished their tumorigenic characteristics in vitro. Further, reduction of CD99 expression resulted in neurite outgrowth and increased expression of beta-III tubulin and markers of neural differentiation. Analysis of a panel of human EWS cells revealed an inverse correlation between CD99 and H-neurofilament expression, as well as an inverse correlation between neural differentiation and oncogenic transformation. As knockdown of CD99 also led to an increase in phosphorylation of ERK1/2, we suggest that the CD99-mediated prevention of neural differentiation of EWS occurs through MAPK pathway modulation. Together, these data indicate a new role for CD99 in preventing neural differentiation of EWS cells and suggest that blockade of CD99 or its downstream molecular pathway may be a new therapeutic approach for EWS.
authors.affiliation: Laboratory of Experimental Oncology, CRS Development of Biomolecular Therapies, SSN Emilia Romagna Istituti Ortopedici Rizzoli IRCCS, Bologna, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rocchi
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Manara
authors.forename: Marika
authors.initials: M
authors.lastname: Sciandra
authors.forename: Diana
authors.initials: D
authors.lastname: Zambelli
authors.forename: Filippo
authors.initials: F
authors.lastname: Nardi
authors.forename: Giordano
authors.initials: G
authors.lastname: Nicoletti
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garofalo
authors.forename: Stefania
authors.initials: S
authors.lastname: Meschini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Astolfi
authors.forename: Mario P
authors.initials: MP
authors.lastname: Colombo
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lessnick
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
mesh_terms: D000071443:12E7 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D001859:Bone Neoplasms; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D009368:Neoplasm Transplantation; D016501:Neurites / Q000378:metabolism* / Q000473:pathology; D016900:Neurofilament Proteins / Q000096:biosynthesis / Q000235:genetics; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D014183:Transplantation, Heterologous
chemical_list: D000071443:12E7 Antigen; D015703:Antigens, CD; C061828:CD99 protein, human; C522605:Cd99 protein, mouse; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D016900:Neurofilament Proteins; C051774:neurofilament protein H; D048052:Mitogen-Activated Protein Kinase 3