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Increased expression of the NME1 gene is associated with metastasis in epithelial ovarian cancer
J A Leary1, J Kerr, G Chenevix-Trench
1Department of Obstetrics and Gynaecology, University of Sydney, NSW, Australia.
Abstract:
The genetic events involved in the development of metastases of epithelial ovarian cancer are largely unknown. One gene postulated to play a role in tumour metastasis suppression is NME1 (nm23-H1), and an inverse relationship between NME1 expression and metastatic potential has been observed for some solid tumours. In this study we have investigated the levels of mRNA expression of the 2 isoforms of the NME gene, NME1 and NME2. A maximum of 45 tumours samples from 33 patients were available for Northern blot analysis. We observed variable levels expression of NME1 and NME2 mRNA. The average level of NME1, but not NME2, mRNA expression was statistically higher in metastatic biopsies when compared with primary tumour biopsies. To examine the possible tumour suppressor gene role of NME1 in ovarian tumours, 76 patients were investigated by Southern blot analysis to determine the rate of allelic deletion. Allele loss at 5 other chromosome 17 loci (D17S5, TP53, NF1, D17S74, D17S4) was also evaluated for many of these 76 patients. Allele loss was observed in 22/30 (73%) informative patients at the NME1 locus. We also observed high rates of allele loss at the other loci evaluated. No correlations with clinical stage, histological subtype or patient survival were observed in either mRNA or DNA analyses. We have established that tumour progression in ovarian cancer is accompanied by over-expression of the NME1 gene; however, despite high rates of allele loss at the NME1 locus, the concept that NME1 may be a candidate tumour suppressor gene in ovarian cancer cannot be confirmed by this study.
Insights
The NME1 gene, or nm23-H1, is over-expressed in metastatic ovarian cancer, contrary to its suspected role as a tumor suppressor. This study found higher NME1 mRNA levels in metastatic tumors, despite significant allele loss at the NME1 locus.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epithelial ovarian cancer metastasis involves unknown genetic events.
- The NME1 (nm23-H1) gene is a candidate for tumor metastasis suppression.
- Previous studies suggest an inverse NME1 expression-metastatic potential link in solid tumors.
Purpose of the Study:
- Investigate NME1 and NME2 mRNA expression levels in epithelial ovarian cancer.
- Determine the role of NME1 as a potential tumor suppressor gene in ovarian cancer.
- Analyze allele deletion rates at the NME1 locus and other chromosome 17 loci.
Main Methods:
- Northern blot analysis to quantify NME1 and NME2 mRNA expression in tumor samples.
- Southern blot analysis to assess allele loss at the NME1 locus.
- Evaluation of allele loss at additional chromosome 17 loci (D17S5, TP53, NF1, D17S74, D17S4).
Main Results:
- NME1 mRNA expression levels were statistically higher in metastatic ovarian cancer biopsies compared to primary tumors.
- NME2 mRNA expression showed variable levels but no significant difference between metastatic and primary tumors.
- High rates of allele loss (73%) were observed at the NME1 locus in informative patients.
Conclusions:
- Tumor progression in ovarian cancer is associated with NME1 gene over-expression.
- Despite high allele loss rates at the NME1 locus, its role as a tumor suppressor gene in ovarian cancer is not confirmed by this study.
- No correlations were found between NME1/NME2 expression or NME1 allele loss and clinical stage, histological subtype, or patient survival.