The Metastasis Suppressor, N-myc Downregulated Gene 1 (NDRG1), Is a Prognostic Biomarker for Human Colorectal Cancer

Mao, Zhihai; Sun, Jing Ping; Feng, Bo; Ma, Junjun; Zang, Lu; Dong, Feng; Zhang, Daohai; Zheng, Min

doi:10.1371/journal.pone.0068206

Cited by 52 publications

(60 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A variety of studies have shown the important role of NDRG1 in inhibiting cancer cell metastasis (Kovacevic and Richardson, 2006;Liu et al, 2011b;Chen et al, 2012;Liu et al, 2012b;Bae et al, 2013;Mao et al, 2013b;Sun et al, 2013a). However, complete understanding of its mechanism of action remains an important research goal.…”

Section: Discussionmentioning

confidence: 99%

The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

Jin¹,

Liu²,

Menezes³

et al. 2014

Journal of Cell Science

Self Cite

123

View full text Add to dashboard Cite

N-myc downstream-regulated gene 1 (NDRG1) is a potent metastasis suppressor that has been demonstrated to inhibit the transforming growth factor b (TGF-b)-induced epithelial-tomesenchymal transition (EMT) by maintaining the cell-membrane localization of E-cadherin and b-catenin in prostate and colon cancer cells. However, the precise molecular mechanism remains unclear. In this investigation, we demonstrate that NDRG1 inhibits the phosphorylation of b-catenin at Ser33/37 and Thr41 and increases the levels of non-phosphorylated b-catenin at the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting b-catenin phosphorylation involves the NDRG1-mediated upregulation of the GSK3b-binding protein FRAT1, which prevents the association of GSK3b with the Axin1-APC-CK1 destruction complex and the subsequent phosphorylation of b-catenin. Additionally, NDRG1 is shown to modulate the WNT-b-catenin pathway by inhibiting the nuclear translocation of b-catenin. This is mediated through an NDRG1-dependent reduction in the nuclear localization of p21-activated kinase 4 (PAK4), which is known to act as a transporter for b-catenin nuclear translocation. The current study is the first to elucidate a unique molecular mechanism involved in the NDRG1-dependent regulation of b-catenin phosphorylation and distribution.

show abstract

Section: Discussionmentioning

confidence: 99%

The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

Jin¹,

Liu²,

Menezes³

et al. 2014

Journal of Cell Science

Self Cite

123

View full text Add to dashboard Cite

show abstract

“…Interestingly, instead of its suppression role in NPC and several other carcinoma, NDRG1 promotes the development or metastasis of lung cancer [10], colon cancer [12], and hepatocellular carcinomas [17]. One possible explanation for these opposite observations is that NDRG1 may use different signaling pathways in different tumor cells to regulate the tumor cell growth, migration and invasive ability.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that NDRG1 plays different roles in different types of tumors. NDRG1 appears to serve as a putative tumor suppressor and is down-regulated in colorectal [11,12], gastric [13], cervical [14], ovarian [15] and prostate [16] cancers.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, NDRG1 expression level correlates with the degree of differentiation of several cancer tissues. NDRG1 expression in poorly differentiated carcinoma is significantly higher than that in well-differentiated carcinoma of the colon [12] and liver [18]. However, the correlation between NDRG1 and Nasopharyngeal carcinoma has not been established.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

NDRG1 attenuates epithelial–mesenchymal transition of nasopharyngeal cancer cells via blocking Smad2 signaling

Xie

Yang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

N-myc downstream-regulated gene 1 (NDRG1) has been implicated in tumorigenesis and metastasis in different cancers. However, its role in nasopharyngeal carcinoma remains unknown. We found that NDRG1 expression level was high in nasopharyngeal cancer 5–8F cells but low in 5–8F-LN cells with lymphatic metastasis potential. Knockdown of NDRG1 by shRNA promoted 5–8F cell proliferation, migration, and invasion in vitro and its tumorigenesis in vivo. Moreover, NDRG1 deficiency induced an epithelial-mesenchymal transition (EMT) of 5–8F cells as shown by an attenuation of E-cadherin and an induction of N-cadherin and vimentin expression. NDRG1 knockdown also enhanced Smad2 expression and phosphorylation. Smad2 signaling was attenuated in 5–8F cells but was significantly activated in 5–8F-LN cells. Knockdown of Smad2 restored E-cadherin but attenuated N-cadherin expression in NDRG1-deficient 5–8F cells, suggesting a reduction of EMT. Consistently, blockade of Smad2 in 5–8F-LN cells increased E-cadherin while diminishing N-cadherin and vimentin expression. These data indicate that Smad2 mediates the NDRG1 deficiency-induced EMT of 5–8F cells. In tumors derived from NDRG1-deficient 5–8F cells, E-cadherin expression was inhibited while vimentin and Smad2 were increased in a large number of cancer cells. Most importantly, NDRG1 expression was attenuated in human nasopharyngeal carcinoma tissues, resulted in a lower survival rate in patients. The NDRG1 was further decreased in the detached nasopharyngeal cancer cells, which was associated with a further reduced survival rate in patients with lymphatic metastasis. Taken together, these results demonstrated that NDRG1 prevents nasopharyngeal tumorigenesis and metastasis via inhibiting Smad2-mediated EMT of nasopharyngeal cells.

show abstract

“…IHC was scored in a double-blinded manner by two authors. The German semi-quantitative scoring system, which takes into consideration the staining intensity and percentage of stained cancer cells, was applied to score NEK2 expression [33]. Staining levels were scored as 0 (no staining), 1 (weak staining), 2 (moderate staining), and 3 (strong staining), according to the staining intensity in the tumor cells.…”

Section: Immunohistochemistry (Ihc) and Ihc Evaluationmentioning

confidence: 99%

The Prognostic Significance of NEK2 in Hepatocellular Carcinoma: Evidence from a Meta-Analysis and Retrospective Cohort Study

Cheng

Chen

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Numerous studies have shown that NIMA-related kinase 2 (NEK2) expression in hepatocellular carcinoma (HCC) tissue is associated with survival and clinicopathological features; however, the evidence remains inconclusive. Thus, we aimed to further explore the prognostic and clinicopathological significance of NEK2 expression in HCC using a two-part study consisting of a retrospective cohort study and a meta-analysis. Methods: In the cohort study, NEK2 expression in 206 HCC samples and adjacent normal liver tissues was detected by immunohistochemistry (IHC). Patients were divided into a high NEK2 expression group and a low NEK2 expression group by the median value of the immunohistochemical scores. The Kaplan–Meier method with the log-rank test was used to analyze survival outcomes in the two groups, and multivariate analysis based on Cox proportional hazard regression models was applied to identify independent prognostic factors. In the meta-analysis, eligible studies were searched in PubMed, EMBASE, Web of Science, and CNKI databases. STATA version 12.0 (Stata Corporation, College Station, TX) was used for statistical analyses. Results: The IHC results of our cohort study showed higher NEK2 expression in HCC tissues compared with adjacent normal liver tissues. Multivariate analysis revealed that high NEK2 expression was an independent risk factor for poor overall survival (OS) [hazard ratio (HR) = 1.763; 95% CI, 1.060–2.935; P = 0.029] and disease-free survival (DFS) [hazard ratio (HR) = 1.687; 95% CI, 1.102–2.584; P = 0.016] in HCC patients. A total of 11 studies with 1,698 patients were enrolled in the meta-analysis, consisting of 10 studies from the database search and our cohort study. The pooled results revealed that high NEK2 expression correlated closely with poor OS among HCC patients (HR = 1.47; 95% CI, 1.21–1.80; P < 0.01), and DFS/recurrence-free survival (RFS) (HR = 1.92; 95% CI, 1.41–2.63; P < 0.01). Additionally, our meta-analysis also showed that the proportion of HCC patients with high NEK2 expression was greater in the group with larger tumors (> 5 cm) than in the group with smaller tumors (≤ 5 cm) [odds ratio (OR) = 2.02; 95% CI, 1.13–3.64; P < 0.01). Conclusion: Our study demonstrated that high NEK2 expression is a risk factor for poor survival in HCC patients. More prospective, homogeneous, and multiethnic studies are required to validate our findings.

show abstract

The Metastasis Suppressor, N-myc Downregulated Gene 1 (NDRG1), Is a Prognostic Biomarker for Human Colorectal Cancer

Cited by 52 publications

References 33 publications

The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

NDRG1 attenuates epithelial–mesenchymal transition of nasopharyngeal cancer cells via blocking Smad2 signaling

The Prognostic Significance of NEK2 in Hepatocellular Carcinoma: Evidence from a Meta-Analysis and Retrospective Cohort Study

Contact Info

Product

Resources

About