title: NEU4L sialidase overexpression promotes β-catenin signaling in neuroblastoma cells, enhancing stem-like malignant cell growth.
abstract: Neuroblastoma (NB) is a frequently lethal tumor that occurs in childhood and originates from embryonic neural crest cells. The malignant and aggressive phenotype of NB is strictly related to the deregulation of pivotal pathways governing the proliferation/differentiation status of neural crest precursor cells, such as MYCN, Delta/Notch and Wnt/β-catenin (CTNNB1) signaling. In this article, we demonstrate that sialidase NEU4 long (NEU4L) influences the differentiation/proliferation behavior of NB SK-N-BE cells by determining hyperactivation of the Wnt/β-catenin signaling pathway. NEU4L overexpression in SK-N-BE cells induced significant increases in active, nonphosphorylated β-catenin content, β-catenin/TCF transcriptional activity and β-catenin gene target expression including MYCN, MYC, CCND2 (cyclin D2) and CDC25A. In turn, these molecular features strongly modified the behavior of NEU4L SK-N-BE overexpressing cells, promoting the following: (1) an enhanced proliferation rate, mainly due to a faster transition from G1 to S phase in the cell cycle; (2) a more undifferentiated cell phenotype, which was similar to stem-like NB cells and possibly mediated by an increase of the expression of the pluripotency genes, MYC, NANOG, OCT-4, CD133 and NES (nestin); (3) the failure of NB cell differentiation after serum withdrawal. The molecular link between NEU4L and Wnt/β-catenin signaling appeared to rely most likely on the capability of the enzyme to modify the sialylation level of cell glycoproteins. These findings could provide a new candidate for therapeutic treatment.
authors.affiliation: Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milan, Segrate, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tringali
authors.forename: Federica
authors.initials: F
authors.lastname: Cirillo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lamorte
authors.forename: Nadia
authors.initials: N
authors.lastname: Papini
authors.forename: Luigi
authors.initials: L
authors.lastname: Anastasia
authors.forename: Barbara
authors.initials: B
authors.lastname: Lupo
authors.forename: Ilaria
authors.initials: I
authors.lastname: Silvestri
authors.forename: Guido
authors.initials: G
authors.lastname: Tettamanti
authors.forename: Bruno
authors.initials: B
authors.lastname: Venerando
mesh_terms: D015153:Blotting, Western; D002450:Cell Communication; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D009439:Neuraminidase / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway
chemical_list: D016895:Culture Media, Serum-Free; D006023:Glycoproteins; C491428:NEU4 protein, human; D009439:Neuraminidase