- Genetic and pharmacological modulation of the MYCN/MAX/MXD network
- Ferrucci, Francesca <1986>
Subject
- BIO/18 Genetica
Description
- MYCN amplification is found in many types of infancy cancer of neuroendocrine origin, including neuroblastoma (NB). Since identification of correlation between MYCN status and poor prognosis, many efforts have been made to develop efficient MYCN targeting drugs. The rationale for choosing MYCN as a NB therapeutic target lies in its tightly controlled expression during embryonic development and its undetectable levels in adult. Moreover, it is found deregulated in highly malignant cancers. Kocak gene arrays highlights that low levels of MYCN antagonists MAX and MNT in presence of MYCN amplification, are related to good clinical outcome. On the other hand, Kocak dataset shows correlation between high levels of MAX and MNT and short term survival probability in NB. We have demonstrated that downregulation of MAX and MNT leads to suppression of the malignant phenotype of MYCN-amplified cells whereas their overexpression leads to enhancement of the malignant NB cell phenotype. To date, despite the attractiveness of MYCN as a therapeutic target and the discovery of new MYCN targeting compounds, most of them have not passed the pre-clinical stage because of their non-specificity. A second approach to counteract MYCN oncogenicity has been proposed and a novel iron chelator M606 was identified for its ability to downregulate MYCN. Role of deacetylation in mediating MYCN downregulation has been shown and activator E2Fs consensus have been found necessary to induce M606-mediated downregulation of a reporter gene under control of MYCN promoter. We further pointed out the role of M606 in inducing hypophosphorylated state of RB supporting the hypothesis of RB sequestration of E2F. A putative role of TGF in mediate M606 downregulation has been suggested. Overall, the present results support the possibility to offset MYCN driven oncogenesis through genetic or pharmacological approaches and provide lines of evidence of deregulated E2F/RB pathways in Neuroblastoma.
Date
- 2017-04-21
Type
- Doctoral Thesis
- PeerReviewed
Format
- application/pdf
Identifier
urn:nbn:it:unibo-20660
Ferrucci, Francesca (2017) Genetic and pharmacological modulation of the MYCN/MAX/MXD network, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Biologia cellulare e molecolare