N-Myc Downstream-Regulated Gene 4 (NDRG4): A Candidate Tumor Suppressor Gene and Potential Biomarker for Colorectal Cancer

被引：173

作者：

Melotte, Veerle ^{[1
]}

Lentjes, Marjolein H. F. M. ^{[1
]}

van den Bosch, Sandra M. ^{[1
]}

Hellebrekers, Debby M. E. I. ^{[1
]}

de hoon, Joep P. J. ^{[1
]}

Wouters, Kim A. D. ^{[1
]}

Daenen, Kathleen L. J. ^{[1
]}

Partouns-Hendriks, Iris E. J. M. ^{[1
]}

Stessels, Filip ^{[1
]}

Louwagie, Joost ^{[4
]}

Smits, Kim M. ^{[2
]}

Weijenberg, Matty P. ^{[2
]}

Sanduleanu, Silvia ^{[3
]}

Khalid-de Bakker, Carolina A. J. ^{[3
]}

Oort, Frank A. ^{[5
]}

Meijer, Gerrit A. ^{[6
]}

Jonkers, Daisy M. A. E. ^{[3
]}

Herman, James G. ^{[7
]}

de Bruine, Adriaan P. ^{[1
]}

van Engeland, Manon ^{[1
]}

机构：

[1] Maastricht Univ, Med Ctr, Dept Pathol, GROW Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands

[2] Maastricht Univ, Med Ctr, Dept Epidemiol, GROW Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands

[3] Maastricht Univ, Dept Internal Med, Div Gastroenterol & Hepatol, NL-6200 MD Maastricht, Netherlands

[4] OncoMethylome Sci SA, Liege, Belgium

[5] Vrije Univ Amsterdam, Med Ctr, Dept Gastroenterol, Amsterdam, Netherlands

[6] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands

[7] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA

来源：

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2009年 / 101卷 / 13期

关键词：

FECAL DNA; PROMOTER METHYLATION; MICROSATELLITE INSTABILITY; COLON-CANCER; CPG ISLAND; HEPATOCELLULAR-CARCINOMA; NETHERLANDS COHORT; PROSTATE-CANCER; BREAST-CANCER; WILMS-TUMOR;

D O I：

10.1093/jnci/djp131

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Identification of hypermethylated tumor suppressor genes in body fluids is an appealing strategy for the noninvasive detection of colorectal cancer. Here we examined the role of N-Myc downstream-regulated gene 4 (NDRG4) as a novel tumor suppressor and biomarker in colorectal cancer. NDRG4 promoter methylation was analyzed in human colorectal cancer cell lines, colorectal tissue, and noncancerous colon mucosa by using methylation-specific polymerase chain reaction (PCR) and bisulfite sequencing. NDRG4 mRNA and protein expression were studied using real-time-PCR and immunohistochemistry, respectively. Tumor suppressor functions of NDRG4 were examined by colony formation, cell proliferation, and migration and invasion assays in colorectal cancer cell lines that were stably transfected with an NDRG4 expression construct. Quantitative methylation-specific PCR was used to examine the utility of NDRG4 promoter methylation as a biomarker in fecal DNA from 75 colorectal cancer patients and 75 control subjects. All P values are two-sided. The prevalence of NDRG4 promoter methylation in two independent series of colorectal cancers was 86% (71/83) and 70% (128/184) compared with 4% (2/48) in noncancerous colon mucosa (P < .001). NDRG4 mRNA and protein expression were decreased in colorectal cancer tissue compared with noncancerous colon mucosa. NDRG4 overexpression in colorectal cancer cell lines suppressed colony formation (P = .014), cell proliferation (P < .001), and invasion (P < .001). NDRG4 promoter methylation analysis in fecal DNA from a training set of colorectal cancer patients and control subjects yielded a sensitivity of 61% (95% confidence interval [CI] = 43% to 79%) and a specificity of 93% (95% CI = 90% to 97%). An independent test set of colorectal cancer patients and control subjects yielded a sensitivity of 53% (95% CI = 39% to 67%) and a specificity of 100% (95% CI = 86% to 100%). NDRG4 is a candidate tumor suppressor gene in colorectal cancer whose expression is frequently inactivated by promoter methylation. NDRG4 promoter methylation is a potential biomarker for the noninvasive detection of colorectal cancer in stool samples.

引用

页码：916 / 927

页数：12

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