Gene Summary

Gene:NDRG1; N-myc downstream regulated 1
Summary:This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein involved in stress responses, hormone responses, cell growth, and differentiation. The encoded protein is necessary for p53-mediated caspase activation and apoptosis. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4D, and expression of this gene may be a prognostic indicator for several types of cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein NDRG1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NDRG1 (cancer-related)

Liu J, Wang T, Creighton CJ, et al.
Nat Commun. 2019; 10(1):2148 [PubMed] Free Access to Full Article Related Publications
Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.

Keller M, Dubois F, Teulier S, et al.
NDR2 kinase contributes to cell invasion and cytokinesis defects induced by the inactivation of RASSF1A tumor-suppressor gene in lung cancer cells.
J Exp Clin Cancer Res. 2019; 38(1):158 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: RASSF1A, a tumor suppressor gene, is frequently inactivated in lung cancer leading to a YAP-dependent epithelial-mesenchymal transition (EMT). Such effects are partly due to the inactivation of the anti-migratory RhoB GTPase via the inhibitory phosphorylation of GEF-H1, the GDP/GTP exchange factor for RhoB. However, the kinase responsible for RhoB/GEF-H1 inactivation in RASSF1A-depleted cells remained unknown.
METHODS: NDR1/2 inactivation by siRNA or shRNA effects on epithelial-mesenchymal transition, invasion, xenograft formation and growth in SCID-/- Beige mice, apoptosis, proliferation, cytokinesis, YAP/TAZ activation were investigated upon RASSF1A loss in human bronchial epithelial cells (HBEC).
RESULTS: We demonstrate here that depletion of the YAP-kinases NDR1/2 reverts migration and metastatic properties upon RASSF1A loss in HBEC. We show that NDR2 interacts directly with GEF-H1 (which contains the NDR phosphorylation consensus motif HXRXXS/T), leading to GEF-H1 phosphorylation. We further report that the RASSF1A/NDR2/GEF-H1/RhoB/YAP axis is involved in proper cytokinesis in human bronchial cells, since chromosome proper segregation are NDR-dependent upon RASSF1A or GEF-H1 loss in HBEC.
CONCLUSION: To summarize, our data support a model in which, upon RASSF1A silencing, NDR2 gets activated, phosphorylates and inactivates GEF-H1, leading to RhoB inactivation. This cascade induced by RASSF1A loss in bronchial cells is responsible for metastasis properties, YAP activation and cytokinesis defects.

de Siqueira LRP, de Moraes Gomes PAT, de Lima Ferreira LP, et al.
Multi-target compounds acting in cancer progression: Focus on thiosemicarbazone, thiazole and thiazolidinone analogues.
Eur J Med Chem. 2019; 170:237-260 [PubMed] Related Publications
Currently, cancer and its progression to metastasis result in a large number of deaths. The lack of new drugs, appropriate clinical trials for metastasis preventive drugs and incomplete understanding of the molecular machinery are the major obstacles in metastasis prevention and treatment. On the other hand, thiosemicarbazones and their bioisosteres, thiazole and thiazolidinone are recurring in a wide range of biologically active compounds that reach different targets within tumor context and represent a promising start point to access potential candidates in metastatic cancer. Therefore, the search for new lead compounds showing highest anticancer potency and less adverse effects is the major challenger in drug discovery. The search was based from 1994 to 2018, focusing on thiosemicarbazone, thiazole and thiazolidinone cores that allowed us to discuss how the three multi-target motifs have been used for the target-based design and development of anticancer agents. In the lasts years, thiosemicarbazone, thiazole, and thiazolidinone cores are recurrent in many approaches for cancer therapy. In our search, it was verified that due to its biodiversity and versatility the anticancer potential of such structures has been assigned to distinct mechanisms reinforcing the value of these cores in the anticancer drug development. The present article aims point out the current application of thiosemicarbazone, thiazole and thiazolidinone cores in the design of anticancer agents within tumor progression, acting via varied targets such as cathepsins, NDRG1 gene and kinases, showing in vitro tests, in vivo tests and clinical trials. In our search it was possible to verify that thiazole is the most studied and the most important of the three structures. Therefore, we hope to provide new insights and valuable inspiration in the research of new drugs and development and contribute to the management of cancer.

Tsui KH, Hou CP, Chang KS, et al.
Metallothionein 3 Is a Hypoxia-Upregulated Oncogene Enhancing Cell Invasion and Tumorigenesis in Human Bladder Carcinoma Cells.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
Metallothioneins have been viewed as modulators in a number of biological regulations regarding cancerous development; however, the function of metallothionein 3 (

Zhang F, Liang D, Lin X, et al.
NDRG1 facilitates the replication and persistence of Kaposi's sarcoma-associated herpesvirus by interacting with the DNA polymerase clamp PCNA.
PLoS Pathog. 2019; 15(2):e1007628 [PubMed] Free Access to Full Article Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV) latently infects host cells and establishes lifelong persistence as an extra-chromosomal episome in the nucleus. To persist in proliferating cells, the viral genome typically replicates once per cell cycle and is distributed into daughter cells. This process involves host machinery utilized by KSHV, however the underlying mechanisms are not fully elucidated. In present study, we found that N-Myc downstream regulated gene 1 (NDRG1), a cellular gene known to be non-detectable in primary B cells and endothelial cells which are the major cell types for KSHV infection in vivo, was highly upregulated by KSHV in these cells. We further demonstrated that the high expression of NDRG1 was regulated by latency-associated nuclear antigen (LANA), the major viral latent protein which tethers the viral genome to host chromosome and plays an essential role in viral genome maintenance. Surprisingly, knockdown of NDRG1 in KSHV latently infected cells resulted in a significant decrease of viral genome copy number in these cells. Interestingly, NDRG1 can directly interact with proliferating cell nuclear antigen (PCNA), a cellular protein which functions as a DNA polymerase clamp during DNA replication. Intriguingly, we found that NDRG1 forms a complex with LANA and PCNA and serves as a scaffold protein bridging these two proteins. We further demonstrated that NDRG1 is critical for mediating LANA to recruit PCNA onto terminal repeat (TR) of KSHV genome, and facilitates viral DNA replication and episome persistence. Taken together, our findings suggest that NDRG1 plays an important role in KSHV viral genome replication, and provide new clues for understanding of KSHV persistence.

Du A, Jiang Y, Fan C
NDRG1 Downregulates ATF3 and Inhibits Cisplatin-Induced Cytotoxicity in Lung Cancer A549 Cells.
Int J Med Sci. 2018; 15(13):1502-1507 [PubMed] Free Access to Full Article Related Publications
N-myc downstream regulated gene 1 (NDRG1) plays a variety of roles in human cancers. Our previous studies showed that NDRG1 expression is elevated in non-small cell lung cancer and contributes to cancer growth. However, its function in apoptosis and chemoresistance in malignant tumors, including lung cancer, is not yet fully understood. In this study, we investigated the roles of NDRG1 in chemoresistance to cisplatin in lung cancer cells. We found that overexpression of NDRG1 significantly reduced cisplatin-induced cytotoxicity in lung cancer A549 cells, while overexpression of activating transcription factor 3 (ATF3), a stress-inducible gene found to be associated with apoptosis in some human cancers, significantly promoted cytotoxicity (

Sheng J, Zhao Q, Zhao J, et al.
SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance.
EBioMedicine. 2018; 38:113-126 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Radioresistance is the major cause of cancer treatment failure. Additionally, splicing dysregulation plays critical roles in tumorigenesis. However, the involvement of alternative splicing in resistance of cancer cells to radiotherapy remains elusive. We sought to investigate the key role of the splicing factor SRSF1 in the radioresistance in lung cancer.
METHODS: Lung cancer cell lines, xenograft mice models, and RNA-seq were employed to study the detailed mechanisms of SRSF1 in lung cancer radioresistance. Clinical tumor tissues and TCGA dataset were utilized to determine the expression levels of distinct SRSF1-regulated splicing isoforms. KM-plotter was applied to analyze the survival of cancer patients with various levels of SRSF1-regulated splicing isoforms.
FINDINGS: Splicing factors were screened to identify their roles in radioresistance, and SRSF1 was found to be involved in radioresistance in cancer cells. The level of SRSF1 is elevated in irradiation treated lung cancer cells, whereas knockdown of SRSF1 sensitizes cancer cells to irradiation. Mechanistically, SRSF1 modulates various cancer-related splicing events, particularly the splicing of PTPMT1, a PTEN-like mitochondrial phosphatase. Reduced SRSF1 favors the production of short isoforms of PTPMT1 upon irradiation, which in turn promotes phosphorylation of AMPK, thereby inducing DNA double-strand break to sensitize cancer cells to irradiation. Additionally, the level of the short isoform of PTPMT1 is decreased in cancer samples, which is correlated to cancer patients' survival.
CONCLUSIONS: Our study provides mechanistic analyses of aberrant splicing in radioresistance in lung cancer cells, and establishes SRSF1 as a potential therapeutic target for sensitization of patients to radiotherapy.

Liu J, Shao Y, He Y, et al.
MORC2 promotes development of an aggressive colorectal cancer phenotype through inhibition of NDRG1.
Cancer Sci. 2019; 110(1):135-146 [PubMed] Free Access to Full Article Related Publications
MORC2 (microrchidia family CW-type zinc finger 2) is a newly identified chromatin remodeling protein that functions in diverse biological processes including gene transcription. NDRG1 is a metastasis suppressor and a prognostic biomarker for colorectal cancer (CRC). However, the relationship between MORC2 and NDRG1 transcriptional regulation and the roles of MORC2 in CRC remain elusive. Here, we showed that MORC2 downregulated NDRG1 mRNA, protein levels, and promoter activity in CRC cells. We also found that MORC2 bound to the -446 to -213 bp region of the NDRG1 promoter. Mechanistically, histone deacetylase sirtuin 1 (SIRT1) was involved in NDRG1 transcriptional regulation. MORC2 was able to interact with SIRT1 and inhibit NDRG1 promoter activity cumulatively with SIRT1. MORC2 overexpression led to a decrease of H3Ac and H4Ac of the NDRG1 promoter. Importantly, we showed that NDRG1 was essential in MORC2-mediated promotion of CRC cell migration and invasion in vitro, as well as lung metastasis of CRC cells in vivo. Moreover, MORC2 expression correlated negatively with NDRG1 expression in CRC patients. High expression of MORC2 was significantly associated with lymph node metastasis (P = 0.019) and poor pTNM stage (P = 0.02) and the expression of MORC2 correlated with poor prognosis in colon cancer patients. Our findings thus contribute to the knowledge of the regulatory mechanism of MORC2 in downregulating NDRG1, and suggest MORC2 as a potential therapeutic target for CRC.

Godbole M, Togar T, Patel K, et al.
Up-regulation of the kinase gene
J Biol Chem. 2018; 293(50):19263-19276 [PubMed] Free Access to Full Article Related Publications
Preoperative progesterone intervention has been shown to confer a survival benefit to breast cancer patients independently of their progesterone receptor (PR) status. This observation raises the question how progesterone affects the outcome of PR-negative cancer. Here, using microarray and RNA-Seq-based gene expression profiling and ChIP-Seq analyses of breast cancer cells, we observed that the serum- and glucocorticoid-regulated kinase gene (

Chen K, Liu XH, Wang FR, et al.
The prognostic value of decreased NDRG1 expression in patients with digestive system cancers: A meta-analysis.
Medicine (Baltimore). 2018; 97(41):e12455 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Digestive system cancers are recognized as associated with high morbidity and mortality. It is generally accepted that N-myc downstream-regulated gene 1 (NDRG1) is aberrantly overexpressed or downregulated in digestive system cancers, and its prognostic value remains controversial. Accordingly, we herein conducted a meta-analysis to explore whether NDRG1 expression is correlated with overall survival (OS) and clinicopathological characteristics of patients with digestive system cancers.
METHODS: We systematically searched PubMed, EMBASE, and Web of Science for eligible studies up to June 6, 2017. In all, 19 publications with 21 studies, were included.
RESULTS: The pooled results showed that low NDRG1 expression was significantly associated with worse OS in colorectal cancer (pooled HR = 1.67, 95% CI: 1.22-2.28, P < .001) and pancreatic cancer (pooled HR = 1.87, 95% CI: 1-3.5, P < .0001). Moreover, the relationships between low NDRG1 expression and higher OS ratio of patients with liver cancer (pooled HR = 0.44, 95% CI: 0.32-0.62, P = .009) and gallbladder cancer (pooled HR = 0.56, 95% CI: 0.23-1.38, P = .01) were observed. Nevertheless, no significant association was observed between low NDRG1 expression and OS in gastric cancer (pooled HR = 0.81, 95% CI: 0.45-1.43, P = .46) or esophageal cancer (pooled HR = 0.76, 95% CI: 0.26-2.24, P = .62).
CONCLUSION: The prognostic significance of NDRG1 expression varies according to cancer type in patients with DSCs. Considering that several limitations existed in this meta-analysis, more studies are required to further assess the prognostic value of NDRG1 expression in patients with DSCs and relevant mechanisms.

Zhao K, Zhao Y, Zhu JY, et al.
A Panel of Genes Identified as Targets for 8q24.13-24.3 Gain Contributing to Unfavorable Overall Survival in Patients with Hepatocellular Carcinoma.
Curr Med Sci. 2018; 38(4):590-596 [PubMed] Related Publications
Copy number aberrations (CNAs) in chromosome arm 8q have been associated with unfavorable clinical outcomes of several cancers and progressive tumor characteristics of hepatocellular carcinoma (HCC). This study was to identify correlation of CNAs in 8q with clinical outcomes of HCC patients, and further screen for differentially expressed genes in outcome-related CNAs. Array comparative genomic hybridization and expression arrays were performed to detect CNAs and expression levels, respectively. The correlations between CNAs in 8q and outcomes were analyzed in 66 patients, with a median follow-up time of 45.0 months (range, 2.6-108.6 months). One hundred and nine cases were further evaluated to identify differentially expressed genes in the potential outcome-related CNAs. Copy number gain in 8q was observed in 22 (33.3%) of the 66 HCC cases. The most recurrent gains (with frequencies >20%) were 8q13.3-21.3,8q21.3-23.3,8q23.3-24.13,8q24.13-24.3, and 8q24.3. Survival analysis showed that 8q24.13-24.3 gain was significantly associated with reduced overall survival (jP=0.010). Multivariate Cox analysis identified 8q24.13-24.3 gain as an independent prognostic factor for poor overall survival (HR=2.47; 95% CI=1.16-5.26; Р=0.019). Apanel of 17 genes within the 8q24.13-24.3 region, including ATAD2,SQLE,PVT1,ASAP1, and NDRG1 were significantly upregulated in HCCs with 8q24.13-24.3 gain compared to those without. These results suggest that copy number gain at 8q24.13-24.3 is an unfavorable prognostic marker for HCC patients, and the potential oncogenes ATAD2,SQLE, PVT1, ASAP1,and NDRG1 within the regional gain, may contribute coordinately to the 8q24.13-24.3 gain-related poor prognosis.

Lingadahalli S, Jadhao S, Sung YY, et al.
Novel lncRNA
Mol Cancer Res. 2018; 16(12):1865-1878 [PubMed] Related Publications
The human genome is mostly transcribed, yielding a rich repository of noncoding transcripts that are involved in a myriad of biological processes including cancer. However, how many noncoding transcripts such as long noncoding RNAs (lncRNA) function in cancer is still unclear. This study identified a novel set of clinically relevant androgen-regulated lncRNAs in prostate cancer. Among this group,

Vaes N, Schonkeren SL, Brosens E, et al.
A combined literature and in silico analysis enlightens the role of the NDRG family in the gut.
Biochim Biophys Acta Gen Subj. 2018; 1862(10):2140-2151 [PubMed] Related Publications
BACKGROUND: The N-Myc Downstream-Regulated Gene (NDRG) family comprises four members that function in cellular processes like proliferation and differentiation. While NDRG1 and NDRG2 are extensively studied, knowledge regarding NDRG3 and NDRG4, despite its recognition as a well-established early-detection marker for colorectal cancer (Cologuard®), is sparse.
SCOPE OF REVIEW: To summarize expression, biomarker potential and functional mechanisms of the NDRGs in the developing, mature and cancerous gut, we combine current literature and in silico analyses from the TCGA-database, GTEX Project, E14.5 mouse intestine and enteric neural crest cells, and an RNA-sequencing time-series of human embryonic colonic samples.
MAJOR CONCLUSIONS: This study reveals that all members display a differential expression pattern in the gut and that NDRG1, NDRG2 and NDRG4 (1) can serve as biomarker for colorectal cancer and (2) have tumor suppressive properties mainly affecting cell proliferation and epithelial-mesenchymal transition.
GENERAL SIGNIFICANCE: Similar effects of the NDRGs on the key-hallmarks of cancer, could implicate analogous functions in other tissue/cancer types.

Sevinsky CJ, Khan F, Kokabee L, et al.
NDRG1 regulates neutral lipid metabolism in breast cancer cells.
Breast Cancer Res. 2018; 20(1):55 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Altered lipid metabolism is an emerging hallmark of aggressive breast cancers. The N-myc downstream regulated gene (NDRG1) gene plays a critical role in peripheral nervous system myelination, as inactivating mutations cause severe demyelinating neuropathy. In breast cancer, elevated NDRG1 expression has been linked to clinical outcomes, but its functional role in breast cancer physiology has remained unclear.
METHODS: A meta-analysis of NDRG1 expression in multiple large publicly available genomic databases was conducted. Genome-wide expression correlation and Cox proportional hazards and Kaplan-Meier modeling of clinical outcomes associated with elevated expression were assessed. To study NDRG1 function, gene silencing and overexpression phenotypic studies were carried out in a panel of cell lines representing all major breast cancer molecular subtypes. Changes in cell proliferation, morphology, and neutral lipid accumulation due to altered NDRG1 expression were assessed by high throughput, quantitative microscopy. Comprehensive lipidomics mass spectrometry was applied to characterize global changes in lipid species due to NDRG1 silencing. Labeled fatty acids were used to monitor cellular fatty acid uptake and subcellular distribution under nutrient replete and starvation culture conditions.
RESULTS: NDRG1 overexpression correlated with glycolytic and hypoxia-associated gene expression, and was associated with elevated rates of metastasis and patient mortality. Silencing NDRG1 reduced cell proliferation rates, causing lipid metabolism dysfunction including increased fatty acid incorporation into neutral lipids and lipid droplets. Conversely, NDRG1 expression minimized lipid droplet formation under nutrient replete and starvation conditions.
CONCLUSIONS: Here we report that NDRG1 contributes to breast cancer aggressiveness by regulating the fate of lipids in cells that exhibit an altered lipid metabolic phenotype. In line with its role in promoting myelination and its association with altered metabolism in cancer, our findings show that NDRG1 is a critical regulator of lipid fate in breast cancer cells. The association between NDRG1 and poor prognosis in breast cancer suggests it should play a more prominent role in patient risk assessment. The function of NDRG1 in breast cancer lipid metabolism may represent a promising therapeutic approach in the future.

Kim SC, Shin YK, Kim YA, et al.
Identification of genes inducing resistance to ionizing radiation in human rectal cancer cell lines: re-sensitization of radio-resistant rectal cancer cells through down regulating NDRG1.
BMC Cancer. 2018; 18(1):594 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Resistance to preoperative radiotherapy is a major clinical problem in the treatment for locally advanced rectal cancer. The role of NDRG1 in resistance to ionizing radiation in rectal cancer has not been fully elucidated. This study aimed to investigate the effect of the reduced intracellular NDRG1 expression on radio-sensitivity of human rectal cancer cells for exploring novel approaches for treatment of rectal cancer.
METHODS: Three radio-resistant human rectal cancer cell lines (SNU-61R80Gy, SNU-283R80Gy, and SNU-503R80Gy) were established from human rectal cancer cell lines (SNU-61, SNU-283, and SNU-503) using total 80 Gy of fractionated irradiation. Microarray analysis was performed to identify differently expressed genes in newly established radio-resistant human rectal cancer cells compared to parental rectal cancer cells.
RESULTS: A microarray analysis indicated the RNA expression of five genes (NDRG1, ERRFI1, H19, MPZL3, and UCA1) was highly increased in radio-resistant rectal cancer cell lines. Short hairpin RNA-mediated silencing of NDRG1 sensitized rectal cancer cell lines to clinically relevant doses of radiation by causing more DNA double strand breakages to rectal cancer cells when exposed to radiation.
CONCLUSIONS: Targeting NDRG1 represents a promising strategy to increase response to radiotherapy in human rectal cancer.

Hu WQ, Wang W, Fang DL, Yin XF
Identification of Biological Targets of Therapeutic Intervention for Hepatocellular Carcinoma by Integrated Bioinformatical Analysis.
Med Sci Monit. 2018; 24:3450-3461 [PubMed] Free Access to Full Article Related Publications
BACKGROUND We screened the potential molecular targets and investigated the molecular mechanisms of hepatocellular carcinoma (HCC). MATERIAL AND METHODS Microarray data of GSE47786, including the 40 μM berberine-treated HepG2 human hepatoma cell line and 0.08% DMSO-treated as control cells samples, was downloaded from the GEO database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed; the protein-protein interaction (PPI) networks were constructed using STRING database and Cytoscape; the genetic alteration, neighboring genes networks, and survival analysis of hub genes were explored by cBio portal; and the expression of mRNA level of hub genes was obtained from the Oncomine databases. RESULTS A total of 56 upregulated and 8 downregulated DEGs were identified. The GO analysis results were significantly enriched in cell-cycle arrest, regulation of transcription, DNA-dependent, protein amino acid phosphorylation, cell cycle, and apoptosis. The KEGG pathway analysis showed that DEGs were enriched in MAPK signaling pathway, ErbB signaling pathway, and p53 signaling pathway. JUN, EGR1, MYC, and CDKN1A were identified as hub genes in PPI networks. The genetic alteration of hub genes was mainly concentrated in amplification. TP53, NDRG1, and MAPK15 were found in neighboring genes networks. Altered genes had worse overall survival and disease-free survival than unaltered genes. The expressions of EGR1, MYC, and CDKN1A were significantly increased, but expression of JUN was not, in the Roessler Liver datasets. CONCLUSIONS We found that JUN, EGR1, MYC, and CDKN1A might be used as diagnostic and therapeutic molecular biomarkers and broaden our understanding of the molecular mechanisms of HCC.

Andersen ME, Cruzan G, Black MB, et al.
Strain-related differences in mouse lung gene expression over a two-year period of inhalation exposure to styrene: Relevance to human risk assessment.
Regul Toxicol Pharmacol. 2018; 96:153-166 [PubMed] Related Publications
Both CD-1 and C57BL/6 wildtype (C57BL/6-WT) mice show equivalent short-term lung toxicity from exposures to styrene, while long-term tumor responses are greater in CD-1 mice. We analyzed lung gene expression from styrene exposures lasting from 1-day to 2-years in male mice from these two strains, including a Cyp2f2(-/-) knockout (C57BL/6-KO) and a Cyp2F1/2A13/2B6 transgenic mouse (C57BL/6-TG). With short term exposures (1-day to 1-week), CD-1 and C57BL/6-WT mice had thousands of differentially expressed genes (DEGs), consistent with changes in pathways for cell proliferation, cellular lipid metabolism, DNA-replication and inflammation. C57BL/6-WT mice responded within a single day; CD-1 mice required several days of exposure. The numbers of exposure related DEGs were greatly reduced at longer times (4-weeks to 2-years) with enrichment only for biological oxidations in C57BL/6-WT and metabolism of lipids and lipoproteins in CD-1. Gene expression results indicate a non-genotoxic, mouse specific mode of action for short-term styrene responses related to activation of nuclear receptor signaling and cell proliferation. Greater tumor susceptibility in CD-1 mice correlated with the presence of the Pas1 loci, differential Cytochrome P450 gene expression, down-regulation of Nr4a, and greater inflammatory pathway activation. Very few exposure-related responses occurred at any time in C57BL/6-KO or -TG mice indicating that neither the short term nor long term responses of styrene in mice are relevant endpoints for assessing human risks.

He L, Liu K, Wang X, et al.
NDRG1 disruption alleviates cisplatin/sodium glycididazole-induced DNA damage response and apoptosis in ERCC1-defective lung cancer cells.
Int J Biochem Cell Biol. 2018; 100:54-60 [PubMed] Related Publications
BACKGROUND: Resistance to platinum-based chemotherapy becomes a major obstacle in lung cancer treatment. Compensatory activation of nucleotide excision repair (NER) pathway is the major mechanism accounting for cisplatin-resistance. We aimed at identifying additional regulators in NER-mediated chemoresistance in a hypoxic setting induced by sodium glycididazole (CMNa)-sensitized cisplatin chemotherapy of non-small cell lung cancer (NSCLC).
METHODS: We performed an RNA-sequencing (RNA-Seq) analysis to identify the genes whose expression had been differentially regulated in NER-deficient cells that had been treated by cisplatin/CMNa. DNA damage, apoptosis, and correlational analysis between the differentially expressed gene and drug sensitivity were determined by Western blots, flow cytometry and Oncomine expression analysis.
RESULTS: The stress response gene, NDRG1 (N-Myc downstream-regulated gene 1), was among the differentially expressed genes in NER-deficient cells upon treatment of cisplatin/CMNa. Downregulation of NDRG1 by ERCC1 (excision repair cross-complementing 1) could be a prevalent mechanism for drug resistance. Furthermore, lower NDRG1 level is observed in human lung cancer cells showing chemotherapeutic drug resistance compared with the drug-sensitive cells.
CONCLUSION: NDRG1 is an important modulator linking DNA damage response and hypoxia-related cellular stress response during the development of drug resistance to cisplatin/CMNa in lung cancer. Targeting both NDRG1 and ERCC1 may be a viable strategy for overcoming drug resistance in cancer therapy, and has significant clinical implications.

Chang CC, Chang YS, Huang HY, et al.
Determination of the mutational landscape in Taiwanese patients with papillary thyroid cancer by whole-exome sequencing.
Hum Pathol. 2018; 78:151-158 [PubMed] Related Publications
Among women in Taiwan, thyroid cancer is the fifth most common malignant neoplasia. However, genomic profiling of papillary thyroid cancer (PTC) cases from Taiwan has not been attempted previously. We used whole-exome sequencing to identify mutations in a cohort of 19 PTC patients. Sequencing was performed using the Illumina system; Sanger sequencing was used to validate all identified mutations. We identified new somatic mutations in APC, DICER1, LRRC8D and NDRG1. We also found somatic mutations in ARID5A, CREB3L2, MDM4, PPP2R5A and TFPT; mutations in these genes had been found previously in other tumors, but had not been described previously in PTC. We also investigated the pathway deregulation in BRAF-mutated PTC compared with wild-type BRAF PTC. In checking our gene mutations against The Cancer Genome Atlas (TCGA) database, we identified aberrations in one pathway that are specific to BRAF-mutated PTC: maturity-onset diabetes of the young. In addition, the caffeine metabolism pathway showed aberrations that are specific to wild-type BRAF PTC. For this study, we performed a comprehensive exome-wide analysis of the mutational spectra of Taiwanese patients with PTC. We identified novel genes that are potentially associated with PTC tumorigenesis, as well as aberrations in pathways that led to the distinct pathogeneses of BRAF-mutated PTC and wild-type BRAF PTC, which may provide a new target for PTC therapy.

Chiang KC, Yang SW, Chang KP, et al.
Caffeic Acid Phenethyl Ester Induces
Int J Mol Sci. 2018; 19(5) [PubMed] Free Access to Full Article Related Publications
Caffeic acid phenethyl ester (CAPE), a bioactive component extracted from propolis, is widely studied due to its anti-cancer effect. Nasopharyngeal carcinoma (NPC) is distinct from other head and neck carcinomas and has a high risk of distant metastases.

Park KC, Menezes SV, Kalinowski DS, et al.
Identification of differential phosphorylation and sub-cellular localization of the metastasis suppressor, NDRG1.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(8):2644-2663 [PubMed] Related Publications
The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), exhibits pleiotropic activity, inhibiting metastasis of various tumor-types, while being correlated with metastasis in others. Notably, NDRG1 phosphorylation and cleavage are associated with its function, although it is unclear if these modifications occur universally, or selectively, in different cancer cell-types and if it contributes to its pleiotropy. Considering the suggested DNA repair role of nuclear NDRG1, the effects of the above post-translational modifications on its nuclear localization was examined. Herein, the full-length (FL) and truncated (T) NDRG1 isoforms were detected using a C-terminus-directed antibody, while only the FL isoform was identified using an N-terminus-directed antibody. For the first time, we demonstrate that the expression of the NDRG1 FL and T forms occurs in all cancer cell-types examined, as does its phosphorylation (p-NDRG1) at Ser330 and Thr346. The FL isoform localized highly in the nucleus compared to the T isoform. Moreover, p-NDRG1 (Ser330) was also markedly localized in the nucleus, while p-NDRG1 (Thr346) was predominantly cytoplasmic in all cell-types. These results indicate the N-terminus region and phosphorylation at Ser330 could be crucial for NDRG1 nuclear localization and function. PTEN silencing indicated that p-NDRG1 (Thr346) could be regulated differentially in different tumor cell-types, indicating PTEN may be involved in the mechanism(s) underlying the pleiotropic activity of NDRG1. Finally, therapeutics of the di-2-pyridylketone thiosemicarbazone class increased nuclear NDRG1 isoforms (FL and T) detected by the C-terminus-directed antibody in HepG2 cells, while having no significant effect in PC3 cells, indicating differential activity depending on the cell-type.

Zhou W, Zhao M
How Hippo Signaling Pathway Modulates Cardiovascular Development and Diseases.
J Immunol Res. 2018; 2018:3696914 [PubMed] Free Access to Full Article Related Publications
Cardiovascular disease remains the leading cause of death around the globe. Cardiac deterioration is associated with irreversible cardiomyocyte loss. Understanding how the cardiovascular system develops and the pathological processes of cardiac disease will contribute to finding novel and preventive therapeutic methods. The canonical Hippo tumor suppressor pathway in mammalian cells is primarily composed of the MST1/2-SAV1-LATS1/2-MOB1-YAP/TAZ cascade. Continuing research on this pathway has identified other factors like RASSF1A, Nf2, MAP4Ks, and NDR1/2, further enriching our knowledge of the Hippo-YAP pathway. YAP, the core effecter of the Hippo pathway, may accumulate in the nucleus and initiate transcriptional activity if the pathway is inhibited. The role of Hippo signaling has been widely investigated in organ development and cancers. A heart of normal size and function which is critical for survival could not be generated without the proper regulation of the Hippo tumor suppressor pathway. Recent research has demonstrated a novel role of Hippo signaling in cardiovascular disease in the context of development, hypertrophy, angiogenesis, regeneration, apoptosis, and autophagy. In this review, we summarize the current knowledge of how Hippo signaling modulates pathological processes in cardiovascular disease and discuss potential molecular therapeutic targets.

Byun JW, An HY, Yeom SD, et al.
NDRG1 and FOXO1 regulate endothelial cell proliferation in infantile haemangioma.
Exp Dermatol. 2018; 27(6):690-693 [PubMed] Related Publications
The etiopathogenesis of infantile haemangioma has not been well understood, and it is accepted that angiogenic mediator dysregulation is the main contributor to the abnormal haemangioma capillary formation. The role of NDRG1, a hypoxia-inducible protein; FOXOs, which are tumor suppressor proteins; and the mTOR complex 2 pathway in infantile haemangioma have not been studied yet. The purpose of this study was to investigate NDRG1 and FOXO1 expression in the infantile haemangioma and the correlation of these proteins with proliferation and involution. Primary endothelial cells were obtained, with parental agreement, from 12 infantile haemangioma patients during surgery; 6 patients had proliferating infantile haemangiomas and 6 had involuting IHs. We compared the infantile haemangioma tissues and primary endothelial cells with human vein endothelial cells using microarrays, real-time PCR, Western blotting and immunohistochemical staining. Our data indicated that FOXO1 expression was downregulated in proliferating infantile haemangioma tissue. We found that the expression of NDRG1, a molecule upstream of the FOXO1 pathway, increased during haemangioma proliferation. NDRG1 knockdown decreased haemangioma endothelial cell proliferation and downregulated c-MYC oncoprotein levels. Our findings suggest that NDRG1 positively regulates haemangioma proliferation. FOXO1 dysregulation plays an important role in infantile haemangiomas pathogenesis.

Wang H, Sun W, Sun M, et al.
HER4 promotes cell survival and chemoresistance in osteosarcoma via interaction with NDRG1.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(5 Pt A):1839-1849 [PubMed] Related Publications
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. The abilities of chemotherapy resistance are major roadblock in the successful treatment of OS. The clarification of mechanism regarding cell survival during OS chemotherapy are important. Here, we examined HER4 expression by immunohistochemistry in a large series of OS tissues, and found HER4 expression correlated with tumor characteristics and patient survival rates. HER4 knockdown by shRNA inhibited OS cell growth and tumorigenesis, and induced cell senescence and apoptosis in vitro and in vivo. We demonstrated that HER4 expression upregulated in the adverse conditions, such as serum starvation and sphere culture. Moreover, HER4 knockdown cells became more sensitive in stressful conditions such as loss of attachment, cytotoxic agents or nutrition insufficiency. Mechanism studies revealed that HER4 interacted with NDRG1, and NDRG1 overexpression could antagonize HER4 knockdown-mediated cell growth and apoptosis in stressed conditions. There was a positive correlation between HER4 and NDRG1 immunoreactivity in OS patients. Together, our present study shows that HER4 and/or NDRG1 might play a critical role for the cell survival and chemo-resistance of OS, and could be used as potential therapeutic targets in OS.

Cruzan G, Bus JS, Andersen ME, et al.
Based on an analysis of mode of action, styrene-induced mouse lung tumors are not a human cancer concern.
Regul Toxicol Pharmacol. 2018; 95:17-28 [PubMed] Related Publications
Based on 13 chronic studies, styrene exposure causes lung tumors in mice, but no tumor increases in other organs in mice or rats. Extensive research into the mode of action demonstrates the key events and human relevance. Key events are: metabolism of styrene by CYP2F2 in mouse lung club cells to ring-oxidized metabolites; changes in gene expression for metabolism of lipids and lipoproteins, cell cycle and mitotic M-M/G1 phases; cytotoxicity and mitogenesis in club cells; and progression to preneoplastic/neoplastic lesions in lung. Although styrene-7,8-oxide (SO) is a common genotoxic styrene metabolite in in vitro studies, the data clearly demonstrate that SO is not the proximate toxicant and that styrene does not induce a genotoxic mode of action. Based on complete attenuation of styrene short-term and chronic toxicity in CYP2F2 knockout mice and similar attenuation in CYP2F1 (humanized) transgenic mice, limited metabolism of styrene in human lung by CYP2F1, 2 + orders of magnitude lower SO levels in human lung compared to mouse lung, and lack of styrene-related increase in lung cancer in humans, styrene does not present a risk of cancer to humans.

Dai T, Dai Y, Murata Y, et al.
The prognostic significance of N-myc downregulated gene 1 in lung adenocarcinoma.
Pathol Int. 2018; 68(4):224-231 [PubMed] Related Publications
It has been reported that N-myc downstream regulated gene 1 (NDRG1) is related to the prognosis of non-small cell lung cancer (NSCLC), and associated with c-Myc degradation in NSCLC cell lines. However, the relationship of NDRG1 to prognosis or c-Myc expression in lung adenocarcinoma has not been well clarified. The present study was designed to investigate the prognostic significance of NDRG1 and/or c-Myc expression in lung adenocarcinoma using immunohistochemistry with a tissue microarray. We examined 184 lung adenocarcinomas and observed low expression of NDRG1 in adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), whereas high expression of NDRG1 was seen in invasive adenocarcinoma. Each of the clinicopathological features except age was significantly correlated with NDRG1 expression. Kaplan-Meier curves indicated that high expression of NDRG1 was significantly correlated with poor prognosis in comparison with low expression (log-rank, P < 0.001). Univariate and multivariate analyses indicated that vascular invasion (P = 0.012), lymphatic permeation (P = 0.038), and NDRG1 expression (P = 0.026) were independent prognostic factors. Expression of NDRG1 and positivity for c-Myc were significantly correlated (P = 0.005). These findings indicate that NDRG1 expression is associated with both prognosis and c-Myc expression in lung adenocarcinoma.

Tiffon C
Histone Deacetylase Inhibition Restores Expression of Hypoxia-Inducible Protein NDRG1 in Pancreatic Cancer.
Pancreas. 2018; 47(2):200-207 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: N-myc downstream-regulated gene-1 (NDRG1) is a hypoxia-inducible and differentiation-related protein and candidate biomarker in pancreatic cancer. As NDRG1 expression is lost in high-grade tumors, the effects of the differentiating histone deacetylase inhibitor trichostatin A (TSA) were examined in human pancreatic cancer cell lines representing different tumor grades.
METHODS: PANC-1 (poorly differentiated) and Capan-1 (moderately to well-differentiated) cells were treated with TSA. Effects were assessed in vitro by microscopic analysis, colorimetric assays, cell counts, real-time polymerase chain reaction, and Western blotting.
RESULTS: Treatment of PANC-1 cells over 4 days with 0.5 μM TSA restored cellular differentiation, inhibited proliferation, and enhanced p21 protein expression. Trichostatin A upregulated NDRG1 mRNA and protein levels under normoxia from day 1 and by 6-fold by day 4 (P < 0.01 at all time points). After 24 hours under hypoxia, NDRG1 expression was further increased in differentiated cells (P < 0.01). Favorable changes were identified in the expression of other hypoxia-regulated genes.
CONCLUSIONS: Histone deacetylase inhibitors offer a potential novel epidrug approach for pancreatic cancer by reversing the undifferentiated phenotype and allowing patients to overcome resistance and better respond to conventional cytotoxic treatments.

Li J, Morinello E, Larsen T, et al.
Carcinogenicity assessment of the Hedgehog pathway inhibitor, vismodegib in Tg.rasH2 mice and Sprague-Dawley rats.
Regul Toxicol Pharmacol. 2018; 92:382-389 [PubMed] Related Publications
Vismodegib (also known as GDC-0449) is a novel small molecule inhibitor of the Hedgehog (Hh) signaling pathway currently approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in humans. Its tumorigenic potential was assessed in dedicated carcinogenicity studies in rasH2 transgenic (Tg.rasH2) mice and Sprague Dawley (SD) rats. Tumorigenicity potential of vismodegib was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas at exposures of ≥0.1-fold and ≥0.6-fold, respectively, of the steady-state exposure (AUC

Luo Q, Wang CQ, Yang LY, et al.
FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells.
Cancer Lett. 2018; 417:21-34 [PubMed] Related Publications
Cancer associated fibroblast (CAF) is a well-known microenvironment contributor for the development of hepatocellular carcinoma (HCC), while forkhead box (FOX) proteins are also critical to exacerbate HCC malignancy. However, whether FOX proteins are involved in the crosstalk between CAFs and HCC cells remains unclear. In the present study, we reveal that CAFs induce forkhead box Q1 (FOXQ1) expression, and N-myc downstream-regulated gene 1 (NDRG1) is therefore trans-activated to enhance HCC initiation. Intriguingly, pSTAT6/C-C motif chemokine ligand 26 (CCL26) signaling is induced by FOXQ1/NDRG1 axis, thus recruiting hepatic stellate cells (HSCs), the main cellular source of CAFs, to the tumor microenvironment. Thereby, tumor initiating properties are enhanced at least partly through a positive feedback loop between CAFs and HCC cells. Importantly, leflunomide, a pSTAT6 inhibitor that has been approved for the treatment of rheumatoid arthritis, significantly blocks the loop and HCC progression. High expression of CAF marker, ACTA2, and induced FOXQ1/NDRG1 axis in HCC tissues predict unfavorable prognosis. Collectively, our findings uncover a positive feedback loop between CAFs and FOXQ1/NDRG1 axis in neoplastic cells to drive HCC initiation, thus providing new potential therapeutic targets for HCC.

Lee E, Wang J, Jung Y, et al.
Reduction of two histone marks, H3k9me3 and H3k27me3 by epidrug induces neuroendocrine differentiation in prostate cancer.
J Cell Biochem. 2018; 119(4):3697-3705 [PubMed] Free Access to Full Article Related Publications
Neuroendocrine prostate cancer (NE PCa) is an aggressive malignancy, often presenting with advanced metastasis. We previously reported that reduction of histone marks regulated by DNMT1 following epidrug (5-Azacitidine, 5-Aza) treatment controls induction of epithelial to mesenchymal (EMT) and a cancer stem cell (CSC) phenotype, which facilitates tumorigenesis in PCa cells. Here, we use the epidrug 5-Aza as a model for how histone marks may regulate the reprogramming of prostate adenocarcinoma into NE phenotypic cells. First, we observed that 5-Aza treatment of PCa cells in vitro induces a neuron-like phenotype. In addition, significant increases in the expression of the NE markers N-Myc downstream regulated gene 1 (NDRG1), enolase-2 (ENO2), and synaptophysin were observed. Critically, a high density of NE cells with synaptophysin expression was found in tumors generated by 5-Aza pretreatment of PCa cells. Importantly, induction of NE differentiation of PCa cells was associated with an enhancement of NDRG1 expression by reduction of two histone marks, H3K9me3 and H3K27me3. Further, more NDRG1 expression was detected in the subset of PCa cells with reduced expression of H3K9me3 or H3K27me3 in the tumors generated by 5-Aza pretreated PCa cells and critically, these biological differences are also observed in small cell carcinoma in advanced stage of human primary PCa tumors. Our results suggest that reduction of histone marks regulated by the epidrug 5-Aza may control induction of a NE phenotype, which facilitates PCa progression. These studies suggest a strong rationale for developing therapeutics, which target epigenetic regulation.

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