Spy1/SpeedyA accelerates neuroblastoma

Contrary to malignant brain tumors arising in adults such as glioma, neuroblastoma develops in young children and is the most common aggressive cancer diagnosed in the first year after birth. Neuroblastoma is an embryonic tumor originating from the migratory neural crest and arises in tissues of the sympathetic nervous system (Maris, N. Engl. Because of its origin, neuroblastoma exhibits a large variety of cell types classified in three main populations (N, S and I). Among them, I type cells are neuroblastoma stem cells with differentiation and malignant potential and are considered " tumor initiating cells " (TIC). They typically express stem cell markers such as CD133 and c-kit, are capable of self renewal, and form fast growing tumors In this context, the balance between proliferation and differentiation of this cell population remains unclear but is tightly linked to the cell cycle progression. Whereas numerous cell cycle regulators are involved in driving proliferation, the recently characterized cyclin-like protein, Spy1 (SpeedyA), is tightly regulated during proliferation of different progenitor cells such as mammary cells or astrocytes (Golipour A et al., Cancer Res. 2008; 68: 3591). Furthermore, Spy1/SpeedyA levels were elevated in malignant human glioma correlating with a poor survival prognosis. To decipher the implication of Spy1/SpeedyA in proliferation of neuroblastoma and its potential role in the TIC, Lubanska et al. analyzed several neuroblastoma cell lines (Lubanska and Porter, Oncoscience. 2014; 1: 336). The expression of Spy1/SpeedyA significantly differs between the tested cell lines, with CHLA-15 and CHLA-20 cell lines expressing higher Spy1/SpeedyA protein levels in comparison to SH-SY5Y cells. In this context, SH-SY5Y treated with retinoic acid to induce neural differentiation displayed a gradual decrease of Spy1/ SpeedyA expression as cells differentiated. This decrease in expression of Spy1/SpeedyA was accompanied by the downregulation of the neural stem cell marker Nestin. Conversely, the overexpression of Spy1/SpeedyA by transient transfection in SH-SY5Y cells resulted in a delay of the induced differentiation, enhancing proliferation as observed by an increased number of cells and increased BrdU and PCNA staining. The lack of differentiation was correlated with increased proliferation of Spy1/SpeedyA overexpressing cells, leading the authors to evaluate the self-renewal capacity of SH-SY5Y cells by their ability to form neurospheres. Overexpression of Spy1/SpeedyA in SH-SY5Y cells increased the number of spheres smaller than 100µm. Moreover, increased expression of Spy1/SpeedyA leads to increased expression of markers for pluripotency (Oct-4), stem cells (Bmi1), glial progenitors (OLIG2), and astrocytes (GFAP). …