Journal
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
Volume 384, Issue 4-5, Pages 489-498Publisher
SPRINGER
DOI: 10.1007/s00210-011-0645-7
Keywords
NM23-H1; Prostate cancer; Nuclear staining; Cytoplasmic staining; Survival analysis; Prognostic marker
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Funding
- AICR UK
- AIRC
- Associazione Italiana Contro la Lotta al Neuroblastoma
- European GRANT FP6-EET pipeline [LSH-CT-2006-037260, HEALTH-F2-2008-201662]
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Nm23-H1 has been identified as a metastatic suppressor gene in murine melanoma cell lines. Several functions have been attributed to its activity in cancer, including a histidine kinase activity, DNA repair, and regulation of other proteins involved in metastatic formation. While in breast cancer, NM23-H1 overexpression indicates a benign status through impairing progression of disease, its function is opposite in other cancers; e.g., neuroblastoma. To further understand this dichotomy of function in cancer, we have analyzed its function in prostate cancer, in which the relationship between NM23-H1 expression and prognostic state is today controversial. In vitro, overexpression of NM23-H1 in PC3 cells inhibited their cell motility, while downregulation of NM23-H1 expression in these cells by RNA interference showed enhanced cell motility. Immunohistochemistry analysis performed on 346 prostate cancer tissue samples showed a relationship between high levels of NM23-H1 expression in the nuclei of these tumorigenic cells and elevated Gleason score, with high levels of NM23-H1 cytoplasmic staining related to metastatic stage. This retrospective survival study demonstrates that high levels of NM23-H1 expression in the cytoplasm determine recurrence of prostate-specific antigen levels only in those patients with metastatic disease. Our findings suggest a correlation between high levels of NM23-H1 protein in the cytoplasm of the cells and progression of prostate cancer to metastasis, thus definitively identifying NM23-H1 as a new negative prognostic marker in prostate cancer.
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