The Role of Aromatic Hydrocarbon Receptor in the Tumorigenesis of Neuroblastoma and Its Relationship With MYCN Expression

This study has been completed.
Sponsor:
Information provided by:
National Taiwan University Hospital
ClinicalTrials.gov Identifier:
NCT01075360
First received: February 23, 2010
Last updated: February 24, 2010
Last verified: February 2010

February 23, 2010
February 24, 2010
August 2008
October 2008   (final data collection date for primary outcome measure)
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Complete list of historical versions of study NCT01075360 on ClinicalTrials.gov Archive Site
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The Role of Aromatic Hydrocarbon Receptor in the Tumorigenesis of Neuroblastoma and Its Relationship With MYCN Expression
The Role of Aromatic Hydrocarbon Receptor in the Tumorigenesis of Neuroblastoma and Its Relationship With MYCN Expression

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.

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Observational
Observational Model: Cohort
Time Perspective: Retrospective
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Non-Probability Sample

From year 1990 to 2009, pediatric neuroblastoma patients treated at National University Hospital, Taiwan

Neuroblastoma
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*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
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April 2009
October 2008   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Neuroblastoma patients with complete follow-up and sufficient samples for study

Exclusion Criteria:

  • Neuroblastoma patients without complete follow-up or sufficient samples for study
Both
up to 18 Years
No
Contact information is only displayed when the study is recruiting subjects
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NCT01075360
200806005R
No
Wen-Ming Hsu, National Taiwan University Hospital
National Taiwan University Hospital
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Study Director: Wen-Ming Hsu,, M.D., Ph.D. National Taiwan University Hospital
National Taiwan University Hospital
February 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP