Deletion of Btg1 Induces Prmt1-Dependent Apoptosis and Increased Stemness in Shh-Type Medulloblastoma Cells Without Affecting Tumor Frequency

• Published in: Frontiers in oncology 2020-03, Vol.10, p.226-226
• Main Authors: Ceccarelli, Manuela, D'Andrea, Giorgio, Micheli, Laura, Tirone, Felice
• Format: Article
• Language: English
• Subjects: apoptosis; cerebellum neurogenesis; medulloblastoma; neoplastic granule cell precursors; Oncology; proliferation; protein arginine methyltransferase 1 (Prmt1)
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2020.00226

About 30% of medulloblastomas (MBs), a tumor of the cerebellum, arise from cerebellar granule cell precursors (GCPs) undergoing transformation following activation of the Sonic hedgehog (Shh) pathway. To study this process, we generated a new MB model by crossing heterozygous ( ) mice, which develop spontaneous Shh-type MBs, with mice lacking B-cell translocation gene 1 ( ), a regulator of cerebellar development. In MBs developing in mice, deletion of does not alter tumor and lesion frequencies, nor affect the proliferation of neoplastic precursor cells. However, in both tumors and lesions arising in mice, ablation of increases by about 25% the apoptotic neoplastic precursor cells, as judged by positivity to activated caspase-3. Moreover, although ablation in early postnatal GCPs, developing in the external granule cell layer, leads to a significant increase of proliferation, and decrease of differentiation, relative to wild-type, no synergy occurs with the mutation. However, deletion greatly increases apoptosis in postnatal GCPs, with strong synergy between -null and mutations. That pronounced increase of apoptosis observed in knockout young or neoplastic GCPs may be responsible for the lack of effect of ablation on tumorigenesis. This increased apoptosis may be a consequence of increased expression of protein arginine methyltransferase 1 (Prmt1) protein that we observe in knockout/ MBs. In fact, apoptotic genes, such as , are targets of Prmt1. Moreover, in -null MBs, we observed a two-fold increase of cells positive to CD15, which labels tumor stem cells, raising the possibility of activation of quiescent tumor cells, known for their role in long-term resistance to treatment and relapses. Thus, appears to play a role in cerebellar tumorigenesis by regulating the balance between apoptosis and proliferation during MB development, also influencing the number of tumor stem cells.