Clinical and pathological significance of N-Myc downstream-regulated gene 2 (NDRG2) in diverse human cancers

Hu, Wei; Yang, Yang; Ma, Zhiqiang; Deng, Chao; Tian, Li; Lv, Jianjun; Yao, Weiwei; Gao, Jianyuan

doi:10.1007/s10495-016-1244-3

Cited by 50 publications

(21 citation statements)

References 73 publications

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“…In this study, NDRG2 was confirmed as a target of miR-486 and NDRG2 expression could be negatively regulated by miR-486. NDRG2 is proposed to be a tumor suppressor gene that plays a key role in the development of diverse human cancers [23][24][25][26]. Interestingly, a previous study had discovered that NDRG2 in the heart is modulated by myocardial I/R and may be involved in I/R-induced cardiac tissue injury [27].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-486 Alleviates Hypoxia-Induced Damage in H9c2 Cells by Targeting NDRG2 to Inactivate JNK/C-Jun and NF-κB Signaling Pathways

Zhang¹,

Zhang²,

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Acute myocardial infarction is a serious disease with high morbidity and mortality. microRNAs (miRNAs) have been proved to play an important role in modulating myocardial ischemia and reperfusion injury. Hence, in this study, we constructed H9c2 cell model to elucidate the roles of microRNA-486 (miR-486) in preventing hypoxia-induced damage in H9c2 cells. Methods: H9c2 cells were cultured in hypoxic incubator with 1% O₂ to simulate hypoxia and/or transfected with miR-486 mimic, scramble, anti-miR-486, si-N-myc downstream-regulated gene 2 (NDRG2) and their corresponding negative controls (NC). Effects of miR-486 and/or NDRG2 dysregulation on hypoxia-induced myocardial injury in H9c2 cells were investigated by evaluating cell viability, migration, invasion and apoptosis using Cell Counting Kit-8 (CCK-8), transwell assay, flow cytometry, respectively. The proteins expression and RNA expression were detected by western blot and quantitative real time polymerase chain reaction (qRT-PCR), respectively. Results: Hypoxia treatment induced damage in H9c2 cells by decreasing cell viability, migration and invasion and increasing cell apoptosis. Moreover, hypoxia inhibited the expression of miR-486 in H9c2 cells. Overexpression of miR-486 alleviated hypoxia-induced myocardial injury in H9c2 cells, while suppression of miR-486 further aggravated hypoxia-induced injury. Furthermore, NDRG2 expression was negatively regulated by miR-486, and NDRG2 was confirmed as a target of miR-486. Knockdown of NDRG2 alleviated the effects of miR-486 suppression on hypoxia-induced myocardial injury. Besides, knockdown of NDRG2 markedly inhibited the activation of c-Jun N-terminal kinase (JNK) /c-jun and nuclear factor κB (NF-κB) signaling pathways in hypoxia-induced H9c2 cells. Conclusion: Our findings indicate that miR-486 may alleviate hypoxia-induced myocardial injury possibly by targeting NDRG2 to inactivate JNK/c-jun and NF-κB signaling pathways. miR-486 may be a potential target for treating ischemic myocardial injury following acute myocardial infarction.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-486 Alleviates Hypoxia-Induced Damage in H9c2 Cells by Targeting NDRG2 to Inactivate JNK/C-Jun and NF-κB Signaling Pathways

Zhang¹,

Zhang²,

Wang

et al. 2018

Cell Physiol Biochem

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“…Additionally, accumulative evidence indicated that overexpression of NDRG2 can significantly inhibit tumor growth, migration, proliferation, adhesion, and invasion. [ 7 , 8 ] Moreover, NDRG2 is reportedly involved in the cellular metabolism processes, such as hormone, ionic, and liquid metabolism, as well as stress responses, such as responses to hypoxia and lipotoxicity. [ 9 – 13 ] NDRG2 expression is decreased in various cancers, including lung, [ 14 ] breast, [ 15 ] colorectal, [ 16 ] hepatocellular, [ 17 ] pancreatic, [ 18 ] and esophageal squamous cancers.…”

Section: Introductionmentioning

confidence: 99%

Low NDRG2 expression predicts poor prognosis in solid tumors

et al. 2020

Medicine

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Background: As a member of the N-myc down-regulated gene family, N-Myc downstream-regulated gene 2 (NDRG2) contributes to the tumorigenesis of various types of cancers. However, the correlation between NDRG2 expression and the prognosis of solid tumor remains to be elucidated because of small sample sizes and inconsistent results in previous studies. In the present study, we conducted a systematic review and meta-analysis to explore the prognostic significance of NDRG2 in human solid tumors. Methods: PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure, and WanFang databases (up to April 2020) were searched for relevant studies that evaluated the impact of NDRG2 on clinical outcomes, including overall survival (OS), and disease-free survival (DFS), in solid tumors. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled to assess the association between NDRG2 expression and the survival of patients with solid tumors. Odds ratios (ORs) with 95% CIs were pooled to estimate the correlation between NDRG2 expression and clinicopathologic characteristics in the patients. Results: A total of 13 eligible studies with 1980 patients were included in this meta-analysis. Low NDRG2 expression was significantly associated with poor OS (HR = 1.96, 95% CI: 1.60–2.40, P < .001) and DFS (HR = 2.70, 95% CI: 1.42–5.13, P = .002) in solid tumor. Furthermore, low NDRG2 expression was related to some phenotypes of tumor aggressiveness, such as clinical stage (OR = 3.21, 95% CI: 1.96–5.26, P < .001), lymph node metastasis (OR = 2.14, 95% CI: 1.49–3.07, P < .001), and degree of differentiation (OR = 0.60, 95% CI: 0.45–0.81, P = .001). Conclusions: NDRG2 may be a meaningful biomarker of poor prognosis and a potential therapeutic target for human solid tumors.

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“…N-Myc downstream-regulated gene 2 (NDRG2) plays an important role in tumor suppression in several cancers or cancer cell lines [1,2]. NDRG2 expression is positively correlated with tumor differentiation but negatively correlated with metastasis and TNM classification of malignant tumors (TNM) stage [3,4,5,6].…”

Section: Introductionmentioning

confidence: 99%

NDRG2 Sensitizes Myeloid Leukemia to Arsenic Trioxide via GSK3β–NDRG2–PP2A Complex Formation

Park

Han

et al. 2019

Cells

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N-Myc downstream-regulated gene 2 (NDRG2) was characterized as a tumor suppressor, inducing anti-metastatic and anti-proliferative effects in several tumor cells. However, NDRG2 functions on anticancer drug sensitivity, and its molecular mechanisms are yet to be fully investigated. In this study, we investigated the mechanism of NDRG2-induced sensitization to As2O3 in the U937 cell line, which is one of the most frequently used cells in the field of resistance to As2O3. NDRG2-overexpressing U937 cells (U937-NDRG2) showed a higher sensitivity to As2O3 than mock control U937 cell (U937-Mock). The higher sensitivity to As2O3 in U937-NDRG2 was associated with Mcl-1 degradation through glycogen synthase kinase 3β (GSK3β) activation. Inhibitory phosphorylation of GSK3β was significantly reduced in U937-NDRG2, and the reduction was diminished by okadaic acid, a protein phosphatase inhibitor. NDRG2 mediated the interaction between GSK3β and protein phosphatase 2A (PP2A), inducing dephosphorylation of GSK3β at S9 by PP2A. Although the C-terminal deletion mutant of NDRG2 (ΔC NDRG2), which could not interact with PP2A, interacted with GSK3β, the mutant failed to dephosphorylate GSK3β at S9 and increased sensitivity to As2O3. Our findings suggest that NDRG2 is a kind of adaptor protein mediating the interaction between GSK3β and PP2A, inducing GSK3β activation through dephosphorylation at S9 by PP2A, which increases sensitivity to As2O3 in U937 cells.

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Clinical and pathological significance of N-Myc downstream-regulated gene 2 (NDRG2) in diverse human cancers

Cited by 50 publications

References 73 publications

MicroRNA-486 Alleviates Hypoxia-Induced Damage in H9c2 Cells by Targeting NDRG2 to Inactivate JNK/C-Jun and NF-κB Signaling Pathways

MicroRNA-486 Alleviates Hypoxia-Induced Damage in H9c2 Cells by Targeting NDRG2 to Inactivate JNK/C-Jun and NF-κB Signaling Pathways

Low NDRG2 expression predicts poor prognosis in solid tumors

NDRG2 Sensitizes Myeloid Leukemia to Arsenic Trioxide via GSK3β–NDRG2–PP2A Complex Formation

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