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Expression analysis of multidrug resistance associated genes in neuroblastomas
P Bader1, F Schilling, M Schlaud
1Children's Hospital, Department of Hematology and Oncology, D-72076 Tubingen, Germany.
Abstract:
In a series of 40 neuroblastomas we analyzed the relative mRNA levels of the MDR associated genes encoding MDR1/P-glycoprotein (MDR1), multidrug resistance associated protein (MRP), lung cancer resistance related protein (LRP) and topoisomerase IIalpha (TOPO IIalpha) by cDNA-PCR. Cyclin A (CYCA) was included to examine cellular proliferation activity. MYCN gene expression was analyzed as it was recently shown to be associated with enhanced MRP gene expression in neuroblastomas. We found that tumors with MYCN gene amplification exhibit significantly increased MYCN and MRP gene expression levels. Tumors with an allelic loss of the chromosomal 1p region showed significant (P<0.05) lower MDR1 gene expression (MDR1: 50+/-29, n=4) than tumors without (MDR1: 117+/-81, P<0.05, n=36). Moreover, significant positive correlations were found for MYCN/TOPO IIalpha (P<0.0001), MYCN/CYCA (P<0.05), TOPO IIalpha/CYCA (P<0.01), MRP/CYCA (P<0.0001) and MRP/LRP (P<0.05). Our results give evidence that MDR in neuroblastomas might be caused by multiple resistance factors and that a higher proliferation rate of neuroblastoma cells possibly based on altered MYCN gene expression is associated with enhanced MRP, CYCA and TOPO IIalpha gene expression.
Insights
Multidrug resistance (MDR) in neuroblastomas involves multiple genes, including MDR1 and MRP. Altered MYCN gene expression correlates with increased proliferation and expression of MRP, CYCA, and TOPO IIalpha, suggesting complex resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neuroblastomas are common childhood cancers.
- Multidrug resistance (MDR) is a significant challenge in neuroblastoma treatment.
- Specific genes like MDR1, MRP, LRP, and TOPO IIalpha are implicated in MDR.
Purpose of the Study:
- To analyze the mRNA levels of MDR-associated genes in neuroblastomas.
- To investigate the relationship between MYCN gene expression, proliferation (CYCA), and MDR genes.
- To explore the role of chromosomal 1p allelic loss on MDR1 expression.
Main Methods:
- Analysis of mRNA levels using cDNA-PCR in 40 neuroblastoma samples.
- Quantification of MDR1, MRP, LRP, TOPO IIalpha, and CYCA gene expression.
- Assessment of MYCN gene amplification and 1p allelic loss.
Main Results:
- Tumors with MYCN amplification showed increased MYCN and MRP expression.
- Loss of 1p allelic region correlated with significantly lower MDR1 expression.
- Positive correlations observed between MYCN/TOPO IIalpha, MYCN/CYCA, TOPO IIalpha/CYCA, MRP/CYCA, and MRP/LRP.
Conclusions:
- MDR in neuroblastomas is likely multifactorial, involving several resistance genes.
- Higher proliferation rates in neuroblastoma cells, potentially linked to MYCN, are associated with increased MRP, CYCA, and TOPO IIalpha expression.
- These findings highlight potential therapeutic targets and prognostic markers in neuroblastoma.
