Down-Regulation of NDRG1 Promotes Migration of Cancer Cells during Reoxygenation

Lai, Liang‐Chuan; Su, Yi Yu; Chen, Kuo Chih; Tsai, Mong-Hsun; Sher, Yuh Pyng; Lu, Tzu-Pin; Lee, Chien Yueh; Chuang, Eric Y.

doi:10.1371/journal.pone.0024375

Cited by 27 publications

(15 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we showed that NDRG1 mRNA expression was downregulated upon re-oxygenation, which is in agreement with a previous study concerning decreased NDRG1 mRNA expression in the breast cancer cell line MCF-7 after re-oxygenation (51). Therefore, NDRG1 is considered to be an O 2 -responsive gene, linked to tumor adaptation towards re-oxygenation (51,52).…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

et al. 2017

View full text Add to dashboard Cite

Abstract. N-myc downstream-regulated gene 1 (NDRG1) is a tumor suppressor with the potential to suppress metastasis, invasion and migration of cancer cells. It is regulated under stress conditions such as starvation or hypoxia. NDRG1 regulation is both induced and controlled by HIF-1α-dependent and -independent pathways under hypoxic conditions. However, there are profound differences in the way NDRG1 expression is regulated by HIF-1α and other transcription factors. Therefore, we aimed to define the time-dependent pattern of NDRG1 mRNA and protein expression in human glioblastoma cell lines in extreme hypoxia and after re-oxygenation as well as under normoxic conditions. Furthermore, we ascribe the regulation of NDRG1 to the transcription factors HIF-1α, SP1, CEBPα, YB-1 and Smad7 in a time-dependent manner. The human malignant glioma cell lines U87-MG, U373 and GaMG were cultured for 1, 6 and 24 h under hypoxic (0.1% O 2 ) conditions and then they were re-oxygenated. The mRNA expression of NDRG1, HIF-1α SP1, CEBPα, YB-1 and Smad7 was measured using semi-quantitative RT-PCR analysis. Their protein expression was analyzed using western blotting. Our experiments revealed that long-term (24 h), but not short-term hypoxia led to the induction of NDRG1 expression in human glioma cell lines. NDRG1 expression was found to correlate with the protein expression of HIF-1α, SP1, CEBPα, YB-1 and Smad7. The present study suggests for the first time that SP1 regulates NDRG1 expression in glioma cells under hypoxia in a time-dependent manner along with HIF-1α, CEBPα, YB-1 and Smad7. These molecules, each separately or in combination, may possess the potential to become target molecules for antitumor therapeutic approaches particularly in human brain tumors.

show abstract

Section: Discussionsupporting

confidence: 93%

“…Therefore, NDRG1 is considered to be an O 2 -responsive gene, linked to tumor adaptation towards re-oxygenation (51,52). However, our western blot results did not support this notion, and suggest posttranscriptional regulation of NDRG1 expression.…”

Section: Discussioncontrasting

confidence: 68%

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Previously, our studies indicated that NDRG1 plays a critical role in tumor adaptation to oxygen fluctuations 39 . Here we provided the first evidence that AHR mediates cobalt-mimetic hypoxia induction of NDRG1 through an AHR/ARNT binding site in the promoter using various promoter truncations or site-mutation constructs.…”

Section: Discussionmentioning

confidence: 90%

Aryl Hydrocarbon Receptor Activates NDRG1 Transcription under Hypoxia in Breast Cancer Cells

Huang

Chang

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

Hypoxia has been intensively investigated over the past several decades based on the observations that hypoxic tumors are more resistant to therapy and have a worse prognosis. Previously, we reported that N-myc downstream-regulated gene 1 (NDRG1) is strongly up-regulated under hypoxia and may play an important role in tumor adaptation to fluctuating oxygen concentrations. However, the regulatory mechanism of NDRG1 under hypoxia remains elusive. Therefore, the purpose of this study was to identify the transcription factors that regulate NDRG1 and to investigate the functional roles of NDRG1 in hypoxia. We showed that binding sites of aryl hydrocarbon receptor (AHR) were predicted in the NDRG1 promoter. Nuclear AHR was up-regulated in the presence of cobalt and hypoxia. AHR translocated to nuclei and bound between base pairs −412 and −388 of the NDRG1 promoter in hypoxia. Moreover, hypoxia-mimetic induction of NDRG1 was attenuated by knockdown of AHR expression. Also, overexpression of AHR facilitated cell proliferation and migration via up-regulation of NDRG1. These results showed for the first time that AHR positively regulates NDRG1 transcription through an AHR binding site by way of hypoxia-mimetic signaling, which may lead to development of a specific therapeutic regimen to prevent tumor malignancy under hypoxia.

show abstract

“…Previously, we used genome-wide expression microarrays to investigate the dynamics of gene profiling during reoxygenation in breast cancer MCF-7 cells, and demonstrated that N-myc downstream-regulated gene 1 ( NDRG1 ) was involved in tumor adaptation to reoxygenation7. NDRG1 is a 43-kD protein composed of 394 amino acids, and is highly conserved among multicellular organisms.…”

mentioning

confidence: 99%

MicroRNA-769-3p Down-regulates NDRG1 and Enhances Apoptosis in MCF-7 Cells During Reoxygenation

Luo

Chang

Sher

et al. 2014

Sci Rep

Self Cite

View full text Add to dashboard Cite

Hypoxia and reoxygenation are common characteristics of solid tumors, which lead to oxidative stress and activation of stress-response genes. Previously, we observed that N-myc downstream-regulated gene 1 (NDRG1) was strongly down-regulated after shifting to reoxygenation, but the regulatory mechanism of NDRG1 remained elusive. Here we focused on the regulation of NDRG1 by microRNAs (miRNAs). Breast cancer MCF-7 cells were cultured under hypoxia for 24 h followed by 24 h of reoxygenation. The miRNA profiles were examined by Nanostring nCounter assays. Forty-three miRNAs had significant changes upon reoxygenation. In silico analysis identified four oxygen-sensitive miRNAs whose seed regions perfectly matched the 3′-UTR of NDRG1. In particular, miR-769-3p was able to inhibit the expression of NDRG1, which caused a significant reduction of NDRG1 protein upon reoxygenation. Furthermore, overexpression of miR-769-3p significantly inhibited cell proliferation and enhanced apoptosis. Our results revealed that miR-769-3p can functionally regulate NDRG1 during changes in oxygen concentration.

show abstract

Down-Regulation of NDRG1 Promotes Migration of Cancer Cells during Reoxygenation

Cited by 27 publications

References 30 publications

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

Aryl Hydrocarbon Receptor Activates NDRG1 Transcription under Hypoxia in Breast Cancer Cells

MicroRNA-769-3p Down-regulates NDRG1 and Enhances Apoptosis in MCF-7 Cells During Reoxygenation

Contact Info

Product

Resources

About