Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children. It is known that overexpression and/or amplification of the MYC oncogene is associated with poor clinical outcome, but the molecular mechanisms and the MYC downstream effectors in MB remain still elusive. Besides contributing to elucidate how progression of MB takes place, most importantly, the identification of novel MYC-target genes will suggest novel candidates for targeted therapy in MB. A group of 209 MYC-responsive genes was obtained from a complementary DNA microarray analysis of a MB-derived cell line, following MYC overexpression and silencing. Among the MYC-responsive genes, we identified the members of the bone morphogenetic protein (BMP) signaling pathway, which have a crucial role during the development of the cerebellum. In particular, the gene BMP7 was identified as a direct target of MYC. A positive correlation between MYC and BMP7 expression was documented by analyzing two distinct sets of primary MB samples. Functional studies in vitro using a small-molecule inhibitor of the BMP/SMAD signaling pathway reproduced the effect of the small interfering RNA-mediated silencing of BMP7. Both approaches led to a block of proliferation in a panel of MB cells and to inhibition of SMAD phosphorylation. Altogether, our findings indicate that high MYC levels drive BMP7 overexpression, promoting cell survival in MB cells. This observation suggests the potential relevance of targeting the BMP/SMAD pathway as a novel therapeutic approach for the treatment of childhood MB.

Suppression of Hepatocyte Proliferation by Hepatocyte Nuclear Factor 4α in Adult Mice

“…It is likely that a transcriptional regulator of Bmp7 is up-regulated after HNF4␣ disruption. A recent report identified BMP7 as a target of MYC (myelocytomatosis oncogene) in medulloblastoma-derived cell lines, binding an unspecified location near the transcription start site (58). Indeed, a small 5.85-fold increase in c-myc mRNA was observed in 9-day Hnf4a F/F;AlbERT2cre knock-out mice.…”

NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma

“…StV-18/02). MB cell lines were cultured as previously published [18,19] and maintained at 37°C in a humidified atmosphere with 5% CO2. DAOY human MB cells were purchased from the American Type Culture Collection (ATCC - Manassas, VA, USA).…”

Epigenetic silencing of miRNA-9 is associated with HES1 oncogenic activity and poor prognosis of medulloblastoma

“…Western blotting analyses were performed as previously published (Fiaschetti et al , 2011). The membranes were incubated with the following first antibodies: HES1 (H-140) (sc-25392, Santa Cruz Biotechnology, Santa Cruz, CA, USA), β -tubulin Class III (TUBB3) (2G10) (Ab78078, Abcam, Cambridge, UK), MASH1/Achaete-scute homolog 1 (ab38557, Abcam), and Cip1/WAF-1/p21 (CP74) (P1484, Sigma-Aldrich, Buchs, Switzerland).…”