N-myc downstream regulated gene-1/Cap43 may play an important role in malignant progression of prostate cancer, in its close association with E-cadherin.
ABSTRACT N-myc downstream regulated gene-1 (NDRG1)/Cap43 plays an important role in tumor progression and metastases in many kinds of cancers. Recently, it was reported that NDRG1/Cap43 is involved in the aggressiveness of prostate cancer and also that its expression is associated with the expression of E-cadherin in prostate carcinoma cell lines. In the current study, to elucidate the functional and pathologic roles of NDRG1/Cap43 in prostate cancer, we investigated whether the expression of NDRG1/Cap43 is associated with the clinicopathologic parameters of prostate cancer or E-cadherin expression. NDRG1/Cap43 expression and E-cadherin expression were examined immunohistochemically in 148 patients with prostate cancer. We investigated the correlation between membranous or cytoplasmic expression of NDRG1/Cap43 and E-cadherin and evaluated the prognostic or clinicopathologic significance of the expression of NDRG1/Cap43. The patients with decreased NDRG1/Cap43 membranous expression showed significantly lower disease-free survival rates compared with the patients with preserved NDRG1/Cap43 membranous expression. Decreased membranous and high cytoplasmic NDRG1/Cap43 expression was also correlated with a higher Gleason score. A significant correlation was observed between NDRG1/Cap43 membranous expression and E-cadherin membranous expression (r = 0.7130; P < .0001) and between NDRG1/Cap43 cytoplasmic expression and E-cadherin cytoplasmic expression (r = 0.5847; P < .0001). Decreased NDRG1/Cap43 membranous expression had a significant impact on patient disease-free survival in multivariate analysis (P = .0175). NDRG1/Cap43 could be a novel marker for malignant progression and poor prognosis in prostate cancer, plausibly in its close association with the down-regulation of E-cadherin expression.
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ABSTRACT: Approximately 30% of clinically localized prostate adenocarcinomas treated by radical prostatectomy (RP) will recur within 10 years. To prevent recurrence, new adjuvant therapies are in development that seek to treat high-risk patients after surgery. To identify patients as candidates for these treatments, improved biomarkers for predicting prognosis are needed. Reduced expression of E-cadherin has been proposed as a new marker for predicting prognosis in prostate adenocarcinoma. Since few studies have examined the relation between risk factors for disease progression and E-cadherin expression using routinely processed RP specimens, we used RP specimens to correlate downregulation of E-cadherin and pathologic stage at RP. Primary adenocarcinomas (n = 76) from formalin-fixed and paraffin-embedded RP specimens were evaluated by immunohistochemistry against E-cadherin (HECD-1) using heat-induced epitope retrieval and automated staining (BioTek Solutions). Normal appearing prostate epithelium was used as an internal control for each specimen. Staining was scored as an estimate of the percentage of tumor cells in each specimen that showed strong plasma membrane staining. Specimens were divided into three categories with respect to Gleason score: intermediate (score 5 to 6, n = 31), intermediate to high (score 7, n = 25), and high (score 8 to 9, n = 20). For pathologic stage, specimens were divided into three categories: low stage/organ confined (pT2, n = 30), intermediate stage/limited extraprostatic extension (pT3a, n = 25), and high stage/seminal vesicle-pelvic lymph node metastases (pT3b-any pTN1, n = 21). In univariate analysis, reduced levels of E-cadherin correlated with advanced Gleason score (P = 0.003) and advanced pathologic stage (P = 0.008). In multivariate analysis, E-cadherin, preoperative prostate-specific antigen, and Gleason score all contributed independently to the prediction of high-stage disease (P<0.0001). Ten pelvic lymph node metastases from this same patient cohort were stained for E-cadherin. All were positive and 9 of 10 were moderately to strongly positive. Since essentially all patients in the high-stage category have a very high likelihood of disease recurrence, we conclude that the study of E-cadherin in a prospective manner as a potential biomarker of disease progression in patients with clinically organ-confined prostate cancer who undergo RP is warranted. Additionally, our finding that most metastatic tumor cells in pelvic lymph nodes express E-cadherin supports the notion that the establishment of the distant colonization and growth of metastatic tumor cells may be facilitated by expression or re-expression of previously downregulated E-cadherin. This would strongly suggest that irreversible genetic inactivation through mutation or allelic loss at 16q2.3 is probably not the mechanism of E-cadherin downregulation in most abnormally expressing primary prostate carcinomas.Urology 04/1999; 53(4):707-13. · 2.42 Impact Factor
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ABSTRACT: The expression of NDRG1 gene is induced by nickel, a transition metal sharing similar physical properties to cobalt. Nickel may create hypoxia-like conditions in cells and induce hypoxia-responsive genes, as does cobalt. Therefore NDRG1 is likely to be another gene induced by hypoxia. HIF-1 is a transcription factor which has a major role in the regulation of hypoxia-responsive genes, and thus it could be involved in the transcriptional regulation of NDRG1 gene. Hypoxia is such a common feature of solid tumours that it is of interest to investigate the expression of Ndrg1 protein in human cancers. Hypoxia and its mimetics induce in vitro expression of NDRG1 gene and cause the accumulation of Ndrg1 protein. Protein levels remain high even after cells revert to normoxia. Although HIF-1 is involved in the regulation of NDRG1, long term hypoxia induces the gene to some extent in HIF-1 knock-out cells. In the majority of human tissues studied, Ndrg1 protein is overexpressed in cancers compared to normal tissues and also reflects tumour hypoxia better than HIF-1 protein. Hypoxia is an inducer of the NDRG1 gene, and nickel probably causes the induction of the gene by interacting with the oxygen sensory pathway. Hypoxic induction of NDRG1 is mostly dependent on the HIF-1 transcription factor, but HIF-1 independent pathways are also involved in the regulation of the gene during chronic hypoxia. The determination of Ndrg1 protein levels in cancers may aid the diagnosis of the disease.BMC Genetics 10/2004; 5:27. · 2.81 Impact Factor
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ABSTRACT: PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been shown to be inactivated in a wide variety of cancers, and the role of this gene as a tumor suppressor has been well established. On the other hand, results of recent animal studies as well as clinical evidence indicate that PTEN is also involved in tumor metastasis suppression. Although PTEN is known to play a key role in controlling cell growth and apoptosis, how PTEN exerts the metastasis suppressor function remains largely unknown. Recently, a microarray analysis identified the Drg-1 gene (differentiation related gene 1) as one of the potential targets of PTEN. The Drg-1 gene has been shown to suppress tumor metastasis in animal models of prostate and colon cancer, and the expression of this gene is significantly reduced with advancement of prostate and breast cancers in clinical setting. In this study, we explored the possibility that PTEN controls tumor metastasis by regulating the expression of the Drg-1 gene. Our results indicate that overexpression of PTEN significantly augments the endogenous expression of Drg-1 protein, whereas inhibition of PTEN by small interfering RNA decreases Drg-1 in a dose- and time-dependent manner. We also found that the control of the Drg-1 gene by PTEN seems to be at the transcriptional level, and that a phospho-Akt inhibitor restores the Drg-1 expression, indicating that PTEN controls Drg-1 by an Akt-dependent pathway. Consistent with these results, our immunohistochemical analysis revealed that PTEN expression correlates significantly with Drg-1 in both prostate and breast cancer cases. Furthermore, combination of the two markers, PTEN and Drg-1, emerged as a significantly better predictor of prostate and breast cancer patient survival than either marker alone.Cancer Research 12/2004; 64(21):7655-60. · 8.65 Impact Factor