|Talk title||Human Embryonic Stem Cells-Derived Neuroblastoma Model Reveals Novel MYCN-amplified Signature Genes Cluster of TWIST1-dependent with Distinct Function in MYCN-amplified Neuroblastomas|
|Speaker||Dr. Zhihui WENG|
|Date & Time||26 March 2019 (Thu)|
|Venue||Room G002, N22 Building (University of Macau)|
|Abstract||MYCN-amplification (MNA) shows a high-risk, aggressive and undifferentiated phenotype in neuroblastomas (NBs). However, the oncogenic basis of MYCN-induced transformation in human neural crest stem cells remains unknown. No studies have been reported on the molecular characteristics from MNA-NB initiation model of human origin. Here, we demonstrate that our hESC-NB model resembles human MNA-neuroblastomas at molecular level. By comparing with the clinical cohort, we clarify the pivotal relationship between clinical cohorts and laboratorial genetic studies to identify novel MYCN-downstream target genes for clinical diagnosis and future drug discovery.|
On top of that, we further verify specific cluster of genes that significantly correlated with MYCN only in MNA neuroblastomas but cannot be defined between MYCN-amplification and non-MYCN-amplification neuroblastomas. We found that these MYCN-amplification signature genes are regulated by MYCN through a TWIST1-dependant manner. MYCN significantly binds to the non-canonical E-box (CANNTG) sequence of promoters to regulate these genes’ expression which is of TWIST1-dependent. We find that MYCN and TWIST1 directly bind to the non-canonical E-box sequence on the promoter of CD55 and regulated CD55 expression. Loss of TWIST1 leads to the lower contribution of MYCN occupancy on non-canonical E-box sequence of CD55 promoter and downregulates CD55 expression. However, MYCN-overexpression cannot rescue CD55 expression in the context of TWIST1-knockdown. We reveal that CD55 exhibits different phenotypes between MNA and non-MNA neuroblastomas in vitro and in vivo. CD55 functions as a cancer stem cell marker in MNA but not in non-MNA neuroblastomas, denoted that CD55 as a MYCN-amplification signature gene plays key role in MNA neuroblastomas depended on the MYCN-amplification-state. All these data indicate that what we had found enlighten novel therapeutic strategies for MNA neuroblastomas.
FHS seminar series by Dr. Zhihui WENG