NDRG4 in gastric cancer determines tumor cell proliferation and clinical outcome

As a novel candidate tumor suppressor, NDRG4 is largely unstudied in human malignancies. In this study, we investigated the protein expression level of NDRG4 in gastric cancer and its association with outcome of patients. In the present study, we recruited 286 patients with gastric cancer and investigated the protein and mRNA expression of NDRG4 in cancer and adjacent normal specimens by immunohistochemistry assay and real‐time PCR. The association of NDRG4 level with clinicopathological characteristics was investigated by appropriate statistical analysis. NDRG4 overexpression and knockdown cell lines were established in order to detect its impact on proliferation and apoptosis. Significant decreased protein and mRNA expression of NDRG4 was found in gastric cancer, compared with adjacent normal specimens. Besides, it was found that NDRG4 protein expression in gastric cancer was significantly associated with tumor differentiation, invasion, metastasis, and stage. Patients with tumors of decreased NDRG4 level were more likely to have unfavorable disease‐free and overall survival, in both univariate and multivariate analysis. In addition, overexpression of NDRG4 suppressed cell proliferation of gastric cancer cells in vitro; conversely, the proliferation of gastric cancer cells were enhanced by knockdown of NDRG4. These results proved for the first time that NDRG4 could be a potential tumor suppressor and prognostic marker of gastric cancer.

[1]  Jian Zhang,et al.  Prediction of Colorectal Cancer Relapse and Prognosis by Tissue mRNA Levels of NDRG2 , 2011, Molecular Cancer Therapeutics.

[2]  N. Xu,et al.  NDRG2 Is a Novel p53-Associated Regulator of Apoptosis in C6-Originated Astrocytes Exposed to Oxygen-Glucose Deprivation , 2013, PloS one.

[3]  William C Hahn,et al.  Lentivirus-delivered stable gene silencing by RNAi in primary cells. , 2003, RNA.

[4]  J. Jaboin,et al.  NDRG4 is a novel oncogenic protein and p53 associated regulator of apoptosis in malignant meningioma cells , 2015, Oncotarget.

[5]  T. Zhong,et al.  Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish. , 2008, Developmental biology.

[6]  B. Angst,et al.  Tbx2 misexpression impairs deployment of second heart field derived progenitor cells to the arterial pole of the embryonic heart. , 2009, Developmental biology.

[7]  Xiao-Fan Wang,et al.  NDRG4 Is Required for Cell Cycle Progression and Survival in Glioblastoma Cells* , 2009, The Journal of Biological Chemistry.

[8]  Qingchuan Zhao,et al.  NDRG4 stratifies the prognostic value of body mass index in colorectal cancer , 2015, Oncotarget.

[9]  Qingchuan Zhao,et al.  NDRG4, a novel candidate tumor suppressor, is a predictor of overall survival of colorectal cancer patients , 2015, Oncotarget.

[10]  T. Miyata,et al.  Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. , 2001, Genomics.

[11]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[12]  Jae-Geun Yoon,et al.  NDRG4 is downregulated in glioblastoma and inhibits cell proliferation. , 2012, Omics : a journal of integrative biology.

[13]  W. Criekinge,et al.  The N‐myc downstream regulated gene (NDRG) family: diverse functions, multiple applications , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[15]  Ga Young Lee,et al.  Potential role of the N-MYC downstream-regulated gene family in reprogramming cancer metabolism under hypoxia , 2016, Oncotarget.

[16]  S. Leeder,et al.  A population based study , 1993, The Medical journal of Australia.

[17]  Gang Li,et al.  Downregulation of N-Myc downstream-regulated gene 4 influences patient survival in gliomas , 2012, Brain Tumor Pathology.

[18]  Y. Jung,et al.  Field Cancerization in Sporadic Colon Cancer , 2016, Gut and liver.

[19]  Jing Liu,et al.  NDRG4 hypermethylation is a potential biomarker for diagnosis and prognosis of gastric cancer in Chinese population , 2016, Oncotarget.

[20]  A. Fukui,et al.  Identification and characterization of Xenopus NDRG1. , 2003, Biochemical and biophysical research communications.

[21]  Ning Wang,et al.  Cancer survival in China, 2003–2005: A population‐based study , 2015, International journal of cancer.

[22]  Fuchu He,et al.  Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family , 2004, Molecular and Cellular Biochemistry.

[23]  A. Jemal,et al.  Cancer statistics in China, 2015 , 2016, CA: a cancer journal for clinicians.

[24]  D. Chu,et al.  Matrix metalloproteinase‐9 is associated with disease‐free survival and overall survival in patients with gastric cancer , 2011, International journal of cancer.

[25]  M. Takeda,et al.  Inhibition of neurite outgrowth by reduced level of NDRG4 protein in antisense transfected PC12 cells. , 2002, Brain research. Developmental brain research.

[26]  T. Miyata,et al.  Differential Expression Patterns of NDRG Family Proteins in the Central Nervous System , 2008, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[27]  M. Westfall,et al.  NDRG1 Is Necessary for p53-dependent Apoptosis* , 2004, Journal of Biological Chemistry.

[28]  T. Miyata,et al.  NDRG4 Protein-deficient Mice Exhibit Spatial Learning Deficits and Vulnerabilities to Cerebral Ischemia* , 2011, The Journal of Biological Chemistry.