Elsevier

Human Pathology

Volume 41, Issue 2, February 2010, Pages 214-222
Human Pathology

Original contribution
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,☆☆

https://doi.org/10.1016/j.humpath.2009.07.011Get rights and content

Summary

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.

Introduction

Prostate cancer is one of the most commonly diagnosed solid cancers [1]. In spite of advances in the detection and treatment of prostate cancer, the mortality rate remains high because current therapeutic strategies are limited in patients with advanced or recurrent cancer. In patients with clinically localized prostate cancer, surgical and radiation treatments are effective; however, a substantial number of patients will experience recurrent disease [2]. The prognosis of patients with prostate cancer is still difficult to predict, and the emergence of effective new approaches for therapy and prognostic markers will depend on the clarification of the mechanisms involved in the progression of this cancer.

The N-myc downstream regulated gene-1 (NDRG1)/Cap43 gene has been identified as a nickel- and calcium-inducible gene [3] that is identical to the differentiation-related gene-1 [4]. The authors of several previous studies have proposed a wide variety of cellular stress response and cell growth regulatory mechanisms that appear to be involved in cellular differentiation [4], [5], proliferation and growth arrest [6], DNA damage response [7], and tumor progression and metastasis [8], [9], [10].

The expression of NDRG1/Cap43 is often elevated in various types of malignant solid tumors, such as the lung, brain, skin, kidney, liver, and breast [11], [12] and endometrial carcinoma [13], compared with their concordant normal tissues. Furthermore, expression of NDRG1/Cap43 was significantly higher in poorly differentiated carcinoma than well-differentiated carcinoma of the colon [14] and liver [15]. However, the authors of other studies have reported that NDRG1/Cap43 expression is augmented in normal cells, as well as well-differentiated cancer cells, and is decreased in poorly differentiated colon, breast, prostate, and pancreatic cancer cells [8], [9], [16], [17], [18]. Several studies have shown that NDRG1/Cap43 expression in cancer cells is a predictive marker of good prognosis in patients with cancers of the prostate, breast, colon, and pancreas [9], [10], [16], [19], whereas its expression is a predictive marker of poor prognosis in patients with liver and cervical cancer [15], [20]. In these studies, NDRG expression was observed in the membrane and the cytoplasm. However, they did not elucidate whether the membranous expression or the cytoplasmic expression should be evaluated. Furthermore, it is controversial whether NDRG1/Cap43 protein is up-regulated or down-regulated in tumor progression.

Altered expression of E-cadherin, which plays important roles in cell1 adhesion, is associated with more aggressive biologic behavior in prostate cancer [21], [22], [23]. Several authors have suggested that NDRG1/Cap43 expression is often associated with E-cadherin expression [8], [24], [25], [26]. Although the interaction between NDRG1/Cap43 and E-cadherin in vitro studies involving normal and malignant cell lines is being clarified, surprisingly, little is known about the specific function of NDRG1/Cap43 and the relation between NDRG1/Cap43 and E-cadherin expression in prostate cancer tissue.

In this study, we examined whether NDRG1/Cap43 expression was closely correlated with clinicopathologic characteristics of prostate cancer or E-cadherin expression in prostate cancer patients who received radical prostatectomy.

Section snippets

Tissues and clinical data

The subjects were 148 patients, who received radical prostatectomy with no chemotherapy or hormonal therapy before surgery and had enough the carcinoma area for the evaluation of immunohistochemistry, at the Kyushu University Hospital, Fukuoka, Japan, between 1997 and 2006. All patients underwent surgery for clinically localized prostate cancer as determined by preoperative prostate-specific antigen (PSA) concentration, digital rectal examination, and prostate needle biopsy. Detailed

NDRG1/Cap43 expression in the membrane, cytoplasm, and nucleus of prostate cancer cells in tumor tissue

NDRG1/Cap43 was predominantly expressed in the membrane of normal prostatic epithelium (Fig. 1A). Membranous expression of NDRG1/Cap43 was preserved in Gleason pattern 3 prostate cancer (Fig. 1B) and decreased in Gleason pattern 5 (Fig. 1C) compared to that in adjacent normal prostatic epithelium. NDRG1/Cap43 was not expressed in the cytoplasm in Gleason pattern 3 prostate cancer (Fig. 1B), but it was strongly expressed in Gleason pattern 5 (Fig. 1C). The median percentage of NDRG1/Cap43

Discussion

To our knowledge, this is the first comprehensive immunohistochemical analysis to reveal the novel knowledge that the NDRG1/Cap43 expression in either the membrane or cytoplasm contributes to Gleason grade and E-cadherin expression in prostate cancer tissue. Membranous NDRG1/Cap43 expression was significantly decreased in higher Gleason score prostate cancer. By contrast, cytoplasmic NDRG1/Cap43 expression was significantly higher in high Gleason score prostate cancer, suggesting that decreased

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    This work was supported by a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (21390107), Tokyo, Japan. The English used in this manuscript was revised by KN International Inc (3 Golf Center, Suite no. 407, Hoffman Estates, IL 60169).

    ☆☆

    The authors declare no disclosures or conflicts of interest.

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