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      Expression of N-Myc Downstream-Regulated Gene 2 in Bladder Cancer and Its Potential Utility as a Urinary Diagnostic Biomarker

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          Abstract

          Background

          Initial diagnosis of carcinoma of the urinary bladder remains challenging. N-Myc downstream-regulated gene 2 ( NDRG2) has been reported to be closely correlated with cell differentiation and proliferation in various cancers. However, its clinical significance in diagnosis of bladder cancer remains unclear. The purpose of this study was to detect the expression of NDRG2 and investigate its diagnostic value in bladder cancer.

          Material/Methods

          We recruited 127 patients with bladder cancer and 97 healthy controls. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting analysis were conducted to measure the NDRG2 expression levels in urine of patients with bladder cancer, bladder cancer cell lines, and healthy controls. The correlations between NDRG2 expression and clinicopathological characteristics were analyzed by chi-square test, and the diagnostic value of NDRG2 was estimated by establishing a receiver operating characteristic (ROC) curve.

          Results

          The relative NDRG2 expression were significantly downregulated both at mRNA and protein levels in urine of patients with bladder cancer and in cell lines, and its low expression was distinctively correlated with tumor grade and stage. The ROC curve showed NDRG2 could be a good diagnostic marker, with an AUC of 0.888, indicating high sensitivity and specificity.

          Conclusions

          NDRG2 was decreased in patients with bladder cancer and might be involved in the progression of this malignancy. Moreover, NDRG2 could be a potential independent diagnostic biomarker for bladder cancer.

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          Most cited references32

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          Bladder cancer.

          Bladder cancer is a heterogeneous disease, with 70% of patients presenting with superficial tumours, which tend to recur but are generally not life threatening, and 30% presenting as muscle-invasive disease associated with a high risk of death from distant metastases. The main presenting symptom of all bladder cancers is painless haematuria, and the diagnosis is established by urinary cytology and transurethral tumour resection. Intravesical treatment is used for carcinoma in situ and other high grade non-muscle-invasive tumours. The standard of care for muscle-invasive disease is radical cystoprostatectomy, and several types of urinary diversions are offered to patients, with quality of life as an important consideration. Bladder preservation with transurethral tumour resection, radiation, and chemotherapy can in some cases be equally curative. Several chemotherapeutic agents have proven to be useful as neoadjuvant or adjuvant treatment and in patients with metastatic disease. We discuss bladder preserving approaches, combination chemotherapy including new agents, targeted therapies, and advances in molecular biology.
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            Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer

            Background While several molecular markers of bladder cancer prognosis have been identified, the limited value of current prognostic markers has created the need for new molecular indicators of bladder cancer outcomes. The aim of this study was to identify genetic signatures associated with disease prognosis in bladder cancer. Results We used 272 primary bladder cancer specimens for microarray analysis and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Microarray gene expression analysis of randomly selected 165 primary bladder cancer specimens as an original cohort was carried out. Risk scores were applied to stratify prognosis-related gene classifiers. Prognosis-related gene classifiers were individually analyzed with tumor invasiveness (non-muscle invasive bladder cancer [NMIBC] and muscle invasive bladder cancer [MIBC]) and prognosis. We validated selected gene classifiers using RT-PCR in the original (165) and independent (107) cohorts. Ninety-seven genes related to disease progression among NMIBC patients were identified by microarray data analysis. Eight genes, a progression-related gene classifier in NMIBC, were selected for RT-PCR. The progression-related gene classifier in patients with NMIBC was closely correlated with progression in both original and independent cohorts. Furthermore, no patient with NMIBC in the good-prognosis signature group experienced cancer progression. Conclusions We identified progression-related gene classifier that has strong predictive value for determining disease outcome in NMIBC. This gene classifier could assist in selecting NMIBC patients who might benefit from more aggressive therapeutic intervention or surveillance.
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              The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications.

              The N-myc downstream regulated gene (NDRG) family of proteins consists of 4 members, NDRG1-4, which are well conserved through evolution. The first member to be discovered and responsible for the family name was NDRG1, because its expression is repressed by the proto-oncogenes MYCN and MYC. All family members are characterized by an α/β hydrolase-fold motif; however, the precise molecular and cellular function of these family members has not been fully elucidated. Although the exact function of NDRG family members has not been clearly elucidated, emerging evidence suggests that mutations in these genes are associated with diverse neurological and electrophysiological syndromes. In addition, aberrant expression as well as tumor suppressor and oncogenic functions affecting key hallmarks of carcinogenesis such as cell proliferation, differentiation, migration, invasion, and stress response have been reported for several of the NDRG proteins. In this review, we summarize the current literature on the NDRG family members concerning their structure, origin, and tissue distribution. In addition, we review the current knowledge regarding the regulation and signaling of the NDRG family members in development and normal physiology. Finally, their role in disease and potential clinical applications (their role as detection or prognostic markers) are discussed.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2017
                27 September 2017
                : 23
                : 4644-4649
                Affiliations
                [1 ]Department of Laboratory Medicine, Shangdong Provincial Hospital Affiliated to Shangdong University, Jinan, Shangdong, P.R. China
                [2 ]Department of Operation, Jinan Hospital, Jinan, Shangdong, P.R. China
                [3 ]Department of Supply, Jinan First People’s Hospital, Jinan, Shangdong, P.R. China
                Author notes
                Corresponding Author: Yueling Wang, e-mail: gkdop34o@ 123456126.com
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                Article
                901610
                10.12659/MSM.901610
                5627538
                28953854
                0b2ca13d-024c-486b-a147-aa6fda4e91c5
                © Med Sci Monit, 2017

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                History
                : 19 September 2016
                : 01 February 2017
                Categories
                Lab/In Vitro Research

                diagnosis, oral,gallbladder neoplasms,genes, vif
                diagnosis, oral, gallbladder neoplasms, genes, vif

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