Tis21-gene therapy inhibits medulloblastoma growth in a murine allograft model

Abstract

Medulloblastoma (MB), the tumor of the cerebellum, is the most frequent brain cancer in childhood and a major cause of pediatric mortality. Based on gene profiling, four MB subgroups have been identified, i.e., Wnt or Sonic Hedgehog (Shh) types, and subgroup 3 or 4. The Shh-type MB has been shown to arise from the cerebellar precursors of granule neurons (GCPs), where a hyperactivation of the Shh pathway leads to their neoplastic transformation. We have previously shown that the gene Tis21 (PC3/Btg2) inhibits the proliferation and promotes the differentiation and migration of GCPs. Moreover, the overexpression or the deletion of Tis21 in Patched1 heterozygous mice, a model of spontaneous Shh-type MB, highly reduces or increases, respectively, the frequency of MB. Here we tested whether Tis21 can inhibit MB allografts. Athymic nude mice were subcutaneously grafted with MB cells explanted from Patched1 heterozygous mice. MB allografts were then injected with adeno-associated viruses either carrying Tis21 (AAV-Tis21) or empty (AAV-CBA). We observed that the treatment with AAV-Tis21 significantly inhibited the growth of tumor nodules, as judged by their volume, and reduced the number of proliferating tumor cells (labeled with Ki67 or BrdU), relative to AAV-CBA-treated control mice. In parallel, AAV-Tis21 increased significantly tumor cells labeled with early and late neural differentiation markers. Overall the results suggest that Tis21-gene therapy slows down MB tumor growth through inhibition of proliferation and enhancement of neural differentiation. These results validate Tis21 as a relevant target for MB therapy.

Piwil1 Regulates Glioma Stem Cell Maintenance and Glioblastoma Progression

“…These data suggest that Piwil1 may help maintain stemness at least in part through Olig2. Silencing Piwil1 also reduced expression of BTG2, the loss of which promotes tumorigenesis in leukemia, medulloblastoma, and oligodendroglioma by regulating differentiation ( Appolloni et al, 2012 ; Dolezal et al, 2017 ; Kuiper et al, 2007 ; Mullighan et al, 2007 ; Presutti et al, 2018 ). In mouse models of GBM, we found that tumors in which Piwil1 was silenced exhibited increased BTG2 expression.…”

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

“…Furthermore, the family-related gene PC3 TIS21/BTG2 is an MB suppressor, as its overexpression inhibits the proliferation and facilitates the differentiation of neoplastic GCPs (40,41). In fact, we found that in a mouse model of spontaneous MB, PC3 TIS21/BTG2 deletion causes a great increase of tumor frequency due to a deficit of GCP migration (42,43).…”

“…In this regard, we have already identified two molecules that act as tumor suppressors of MB, PC3 TIS21/BTG2 (40,41) and Cxcl3 (74). Then, in this report, we investigated the role in the MB pathogenesis of the PC3 TIS21/BTG2 -related gene Btg1, which we have previously shown to be required for the development and function of the cerebellum by operating basically as a negative regulator of the proliferation of cerebellar cell precursors (GCPs) through inhibition of cyclin D1 (12).…”

Profound downregulation of neural transcription factor Npas4 and Nr4a family in fetal mice neurons infected with Zika virus

“…Primers for TATA-box binding protein (TBP) and eukaryotic translation elongation factor 2 (eEF2) were used as internal controls as previously described [57][58][59]. qPCR conditions were as follows: 95˚C for 5 minutes followed by 49 cycles of 95˚C for 10 seconds, 60˚C for 15 seconds, 72˚C for 5 seconds.…”