Sialidase Neu4L overexpression up-regulates Wnt/beta catenin signaling in SK-N-BE neiroblastoma cells, promoting the proliferation on undifferentiated neuroblasts

Neuroblastoma (NB) is a frequently lethal tumor of childhood which originates from embryonic neural crest cells. The malignant and aggressive phenotype of NB is strictly related to the de-regulation of pivotal pathways governing the proliferation/differentiation status of neural crest precursor cells, such as MYCN, Delta/Notch, Wnt/β-catenin (CTNNB1) signaling. In this article, we demonstrated that sialidase Neu4L influences the differentiation/proliferation behavior of NB SK-N-BE cells, determining an hyper-activation of the Wnt/ß-catenin signaling pathway. NEU4L over-expression in SK-N-BE cells induced a significant increase of active, non-phosphorylated β-catenin content, of β-catenin/TCF transcriptional activity, and of β-catenin gene target expression, MYCN, MYC, CCND2 (cyclin D2). In turn, these molecular features deeply modified the behavior of NEU4L SK-N-BE over-expressing cells, promoting: a) an enhanced proliferation rate, mainly due to a faster transition from G1 to S cell cycle phase; b) a more undifferentiated cell phenotype similar to stem-like NB cells, possibly mediated by an increase of the expression of the pluripotency genes, MYC, NANOG, OCT-4, CD133, NES (nestin); c) the failure of NB cell differentiation after serum withdrawal. The molecular link between Neu4L and the Wnt/β-catenin signaling most likely seemed to rely on the capability of the enzyme to modify the sialylation level of cell glycoproteins. In conclusion, NB cells may deregulate Wnt/β-catenin signaling and other related oncogenic genes altering NEU4L expression and activity. These findings could provide a new potential candidate for therapeutic treatment.