Ignite Creation Date:
2024-05-05 @ 10:17 PM
Last Modification Date:
2024-10-26 @ 10:16 AM
Study NCT ID:
NCT01075360
Status:
COMPLETED
Last Update Posted:
2010-02-25
First Post:
2010-02-23
Brief Title:
The Role of Aromatic Hydrocarbon Receptor in the Tumorigenesis of Neuroblastoma and Its Relationship With MYCN Expression
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
The Role of Aromatic Hydrocarbon Receptor in the Tumorigenesis of Neuroblastoma and Its Relationship With MYCN Expression
Status:
COMPLETED
Status Verified Date:
2010-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Neuroblastoma NB is the most common malignant tumor of infancy Approximately 60 of NB patients are clinically diagnosed as the stage IV disease and have a very poor prognosis with the 5-year survival rate no more than 30 Molecular markers of NB have great impacts on the tumor behavior MYCN amplification is the most well-known marker to predict a poor outcome in NB patients However how MYCN affects the NB cell behavior remains unknown In our preliminary studies we performed a genome-wide analysis of the differential gene expression in 10 NB tumors with MYCN amplification and 10 with normal MYCN copy number We found that aromatic hydrocarbon receptor AHR reversely correlated with the MYCN expression This relationship was verified in 83 NB tumor samples In addition positive AHR expression by immunostaining of NB tumors predicted a favorable prognosis These lines of evidence demonstrate that AHR not only relates to the MYCN expression but also plays an important role in the tumorigenesis of NB Therefore in this project we aim at further studying the relationship between AHR and MYCN In addition the possible role of AHR in the tumorigenesis of NB will be clarified Specifically we propose a 3-year project with the following three aims
Aim I Determine the molecular relationship between AHR and MYCN expression AHR has been shown to suppress the E2F1 expression E2F1 reversely has been found to upregulate the expression of MYCN In our preliminary microarray study we also found that the expression E2F1 positively correlated with the MYCN expression but inversely correlated with the expression of AHR Therefore NB cells will be transfected with AHR expression vector or AHR siRNA then the associated E2F1 and MYCN expression will be examined to clarify if AHR could regulate MYCN expression via E2F1 Furthermore the E2F1 levels will also be manipulated to determine if the effect of AHR on MYCN depends on E2F1 In addition the E2F1 expression in NB tumor samples will also be examined to clarify its in vivo role
Aim II Determine the effect of AHR expression on the NB cell behavior The baseline AHR expression levels in several NB cell lines will be examined AHR is then overexpressed by gene transfection in NB cells The cell proliferation migration and differentiation after AHR overexpression are evaluated Furthermore the AHR expression in normal neuron cells is also examined and suppressed by siRNA to if downregulation of AHR could lead to cancer development
Aim III Determine if AHR could be a target of gene therapy for NB NB cells with either normal MYCN or MYCN amplification before and after AHR gene transfection are inoculated into nude mice to demonstrate the effect of AHR expression on NB cells behavior in vivo AHR is then transfected into the wild type NB tumor to see if the tumor growth could be suppressed by AHR expression Then wild type tumor and tumors transfected with AHR are subjected microarray analysis to compare with the human tumor data set for evaluation of gene expression changes along with differential AHR expression Altogether our studies will not only establish the relationship between AHR and MYCN but also allow us to depict the functional role of AHR-MYCN interaction in the tumorigenesis of NB
Aim I Determine the molecular relationship between AHR and MYCN expression AHR has been shown to suppress the E2F1 expression E2F1 reversely has been found to upregulate the expression of MYCN In our preliminary microarray study we also found that the expression E2F1 positively correlated with the MYCN expression but inversely correlated with the expression of AHR Therefore NB cells will be transfected with AHR expression vector or AHR siRNA then the associated E2F1 and MYCN expression will be examined to clarify if AHR could regulate MYCN expression via E2F1 Furthermore the E2F1 levels will also be manipulated to determine if the effect of AHR on MYCN depends on E2F1 In addition the E2F1 expression in NB tumor samples will also be examined to clarify its in vivo role
Aim II Determine the effect of AHR expression on the NB cell behavior The baseline AHR expression levels in several NB cell lines will be examined AHR is then overexpressed by gene transfection in NB cells The cell proliferation migration and differentiation after AHR overexpression are evaluated Furthermore the AHR expression in normal neuron cells is also examined and suppressed by siRNA to if downregulation of AHR could lead to cancer development
Aim III Determine if AHR could be a target of gene therapy for NB NB cells with either normal MYCN or MYCN amplification before and after AHR gene transfection are inoculated into nude mice to demonstrate the effect of AHR expression on NB cells behavior in vivo AHR is then transfected into the wild type NB tumor to see if the tumor growth could be suppressed by AHR expression Then wild type tumor and tumors transfected with AHR are subjected microarray analysis to compare with the human tumor data set for evaluation of gene expression changes along with differential AHR expression Altogether our studies will not only establish the relationship between AHR and MYCN but also allow us to depict the functional role of AHR-MYCN interaction in the tumorigenesis of NB
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None