Gene Summary

Gene:NR4A2; nuclear receptor subfamily 4 group A member 2
Aliases: NOT, RNR1, HZF-3, NURR1, TINUR
Summary:This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. The encoded protein may act as a transcription factor. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson disease, schizophernia, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:nuclear receptor subfamily 4 group A member 2
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (34)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Tumor Burden
  • Messenger RNA
  • Transcription Factors
  • Immunohistochemistry
  • Apoptosis
  • Western Blotting
  • Gene Expression Profiling
  • Protein Binding
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Cancer RNA
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Staging
  • Aldosterone
  • Cervical Cancer
  • Nuclear Proteins
  • Receptors, Thyroid Hormone
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • DNA-Binding Proteins
  • Antineoplastic Agents
  • Nuclear Receptor Subfamily 4, Group A, Member 3
  • Oligonucleotide Array Sequence Analysis
  • Mutation
  • Biomarkers, Tumor
  • Lung Cancer
  • Gene Expression Regulation
  • Point Mutation
  • NR4A2
  • Zona Glomerulosa
  • Colorectal Cancer
  • beta Catenin
  • Transfection
  • Gene Expression
  • Oncogene Fusion Proteins
  • Chromosome 2
  • Cell Proliferation
  • Adrenocortical Cancer
  • Neoplastic Cell Transformation
  • Cancer Gene Expression Regulation
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: NR4A2 (cancer-related)

Shen F, Liu P, Xu Z, et al.
CircRNA_001569 promotes cell proliferation through absorbing miR-145 in gastric cancer.
J Biochem. 2019; 165(1):27-36 [PubMed] Related Publications
Gastric cancer severely threatens human life, while its pathogenesis is still unclear. The present study was to explore the potential pathogenic mechanism underlying gastric cancer. Real-time PCR was performed to detect the expression of circRNA_001569 and miR-145; western blot was performed to detect the expression of NR4A2. Cell cycle and apoptosis was determined using flow cytometry, and cell viability was determined using Cell counting kit-8 (CCK-8) assay. Luciferase reporter assay was carried out to validate the relationship between miR-145 and NR4A2. Both circRNA_001569 and NR4A2 were overexpressed in tissues and cells of gastric cancer, while miR-145 was down-regulated. Overexpressed circRNA_001569 significantly increased cell viability, and decreased cell apoptosis, while down-regulated circRNA_001569 dramatically decreased cell viability and promoted cell apoptosis. CircRNA_001569 regulated the expression of miR-145, the effect of pcDNA-circRNA_001569 was abolished by miR-145 mimic and the effect of si-circRNA_001569 was abolished by miR-145 inhibitor. MiR-145 targets NR4A2 to regulate its expression. Overexpressed miR-145 suppressed cell viability and promoted cell apoptosis. Taken together, the present study indicated that overexpressed circRNA_001569 promoted cell viability of gastric cancer through suppressing the expression of miR-145, which was mediated by NR4A2. The research will provide great theoretical basis for further clinical diagnosis and therapy.

Wu L, Amarachintha S, Xu J, et al.
Mesenchymal COX2-PG secretome engages NR4A-WNT signalling axis in haematopoietic progenitors to suppress anti-leukaemia immunity.
Br J Haematol. 2018; 183(3):445-456 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The bone marrow (BM) microenvironment (niche) plays important roles in supporting normal/abnormal haematopoiesis. We investigated the interaction between leukaemic mesenchymal niche and haematopoietic stem and progenitor cells (HSPCs) using the model of Fanconi anaemia (FA), a genetic disorder characterized by BM failure and leukaemia. Healthy donor HSPCs co-cultured on mesenchymal stromal cells (MSCs) derived from FA patients with acute myeloid leukaemia (AML) exhibited higher human engraftment and myeloid expansion in Non-obese diabetic severe combined immunodeficiency IL-2γ

Vastrad C, Vastrad B
Bioinformatics analysis of gene expression profiles to diagnose crucial and novel genes in glioblastoma multiform.
Pathol Res Pract. 2018; 214(9):1395-1461 [PubMed] Related Publications
Therefore, the current study aimed to diagnose the genes associated in the pathogenesis of GBM. The differentially expressed genes (DEGs) were diagnosed using the limma software package. The ToppFun was used to perform pathway and Gene Ontology (GO) enrichment analysis of the DEGs. Protein-protein interaction (PPI) networks, extracted modules, miRNA-target genes regulatory network and miRNA-target genes regulatory network were used to obtain insight into the actions of DEGs. Survival analysis for DEGs carried out. A total of 701 DEGs, including 413 upregulated and 288 downregulated genes, were diagnosed between U1118MG cell line (PK 11195 treated with 1 h exposure) and U1118MG cell line (PK 11195 treated with 24 h exposure). The up-regulated genes were enriched in superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis, cell cycle, cell cycle process and chromosome. The down-regulated genes were enriched in folate transformations I, biosynthesis of amino acids, cellular amino acid metabolic process and vacuolar membrane. The current study screened the genes in PPI network, extracted modules, miRNA-target genes regulatory network and miRNA-target genes regulatory network with higher degrees as hub genes, which included MYC, TERF2IP, CDK1, EEF1G, TXNIP, SLC1A5, RGS4 and IER5L Survival suggested that low expressed NR4A2, SLC7 A5, CYR61 and ID1 in patients with GBM was linked with a positive prognosis for overall survival. In conclusion, the current study could improve our understanding of the molecular mechanisms in the progression of GBM, and these crucial as well as new molecular markers might be used as therapeutic targets for GBM.

Mlak R, Powrózek T, Brzozowska A, et al.
RRM1 gene expression evaluated in the liquid biopsy (blood cfRNA) as a non-invasive, predictive factor for radiotherapy-induced oral mucositis and potential prognostic biomarker in head and neck cancer patients.
Cancer Biomark. 2018; 22(4):657-667 [PubMed] Related Publications
BACKGROUND: Intensified treatment of head and neck cancers (HNC): by radiotherapy (RTH) commonly combined with cytotoxic drugs is associated with oral mucositis (OM). Changes in the functioning of nucleotide synthesis pathway (RNR1, coded by RRM1 gene) can modulate the efficiency of cellular DNA repair mechanisms and influence the risk of occurrence and severity of OM in HNC patients after RTH.
OBJECTIVE: The objective of this study was to evaluate the correlation between expression of RRM1 gene measured in free circulating RNA (cfRNA) and the risk of more severe OM and disease-free survival (DFS) and overall survival (OS) in patients undergoing RTH for HNC.
METHODS: The study included 60 patients treated with RTH for HNC. RRM1 gene expression was examined in circulating RNA isolated from peripheral blood plasma (before treatment).
RESULTS: High RRM1 gene expression was significantly associated with higher risk of grade 3 OM after 5 (OR = 4.97), 6 (OR = 4.33) and 7 (OR = 3.50) weeks of RTH. Expression of RRM1 gene was not significantly related with risk of DFS and OS shortening (however well separated Kaplan-Meier curves might suggest its potential prognostic impact).
CONCLUSIONS: The evaluation of RRM1 gene expression in cfRNA allows for estimation of the risk of severe OM in patients subjected to RTH.

Hacker B, Schultheiß C, Döring M, Kurzik-Dumke U
Molecular partners of hNOT/ALG3, the human counterpart of the Drosophila NOT and yeast ALG3 gene, suggest its involvement in distinct cellular processes relevant to congenital disorders of glycosylation, cancer, neurodegeneration and a variety of further pathologies.
Hum Mol Genet. 2018; 27(11):1858-1878 [PubMed] Related Publications
This study provides first insights into the involvement of hNOT/ALG3, the human counterpart of the Drosophila Neighbour of TID and yeast ALG3 gene, in various putative molecular networks. HNOT/ALG3 encodes two translated transcripts encoding precursor proteins differing in their N-terminus and showing 33% identity with the yeast asparagine-linked glycosylation 3 (ALG3) protein. Experimental evidence for the functional homology of the proteins of fly and man in the N-glycosylation has still to be provided. In this study, using the yeast two-hybrid technique we identify 17 molecular partners of hNOT-1/ALG3-1. We disclose the building of hNOT/ALG3 homodimers and provide experimental evidence for its in vivo interaction with the functionally linked proteins OSBP, OSBPL9 and LRP1, the SYPL1 protein and the transcription factor CREB3. Regarding the latter, we show that the 55 kDa N-glycosylated hNOT-1/ALG3-1 molecule binds the N-glycosylated CREB3 precursor but does not interact with CREB3's proteolytic products specific to the endoplasmic reticulum and to the nucleus. The interaction between the two partners is a prerequisite for the proteolytic activation of CREB3. In case of the further binding partners, our data suggest that hNOT-1/ALG3-1 interacts with both OSBPs and with their direct targets LRP1 and VAMP/VAP-A. Moreover, our results show that various partners of hNOT-1/ALG3-1 interact with its diverse post translationally processed products destined to distinct cellular compartments. Generally, our data suggest the involvement of hNOT-1/ALG3-1 in various molecular contexts determining essential processes associated with distinct cellular machineries and related to various pathologies, such as cancer, viral infections, neuronal and immunological disorders and CDG.

Kokosar M, Benrick A, Perfilyev A, et al.
A Single Bout of Electroacupuncture Remodels Epigenetic and Transcriptional Changes in Adipose Tissue in Polycystic Ovary Syndrome.
Sci Rep. 2018; 8(1):1878 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
A single bout of electroacupuncture results in muscle contractions and increased whole body glucose uptake in women with polycystic ovary syndrome (PCOS). Women with PCOS have transcriptional and epigenetic alterations in the adipose tissue and we hypothesized that electroacupuncture induces epigenetic and transcriptional changes to restore metabolic alterations. Twenty-one women with PCOS received a single bout of electroacupuncture, which increased the whole body glucose uptake. In subcutaneous adipose tissue biopsies, we identified treatment-induced expression changes of 2369 genes (Q < 0.05) and DNA methylation changes of 7055 individual genes (Q = 0.11). The largest increase in expression was observed for FOSB (2405%), and the largest decrease for LOC100128899 (54%). The most enriched pathways included Acute phase response signaling and LXR/RXR activation. The DNA methylation changes ranged from 1-16%, and 407 methylation sites correlated with gene expression. Among genes known to be differentially expressed in PCOS, electroacupuncture reversed the expression of 80 genes, including PPARγ and ADIPOR2. Changes in the expression of Nr4a2 and Junb are reversed by adrenergic blockers in rats demonstrating that changes in gene expression, in part, is due to activation of the sympathetic nervous system. In conclusion, low-frequency electroacupuncture with muscle contractions remodels epigenetic and transcriptional changes that elicit metabolic improvement.

Li X, Wang B, Tang L, et al.
GSTA1 Expression Is Correlated With Aldosterone Level in KCNJ5-Mutated Adrenal Aldosterone-Producing Adenoma.
J Clin Endocrinol Metab. 2018; 103(3):813-823 [PubMed] Related Publications
Context: KCNJ5 mutation is a major cause of aldosterone-producing adenomas (APAs). The development of APA apart from KCNJ5 mutation is less investigated.
Objective: To investigate other mechanisms affecting aldosterone secretion apart from KCNJ5.
Patients and Methods: Six pairs of KCNJ5-mutated, high and low aldosterone-secreting APAs, five non-KCNJ5-mutated APAs, and four normal adrenal glands were assayed by Affymetrix GeneChip Human Transcriptome Array 2.0. A total of 113 APA samples were investigated to explore the expression of glutathione-S-transferase A1 (GSTA1). H295R cells were used to verify the function of GSTA1.
Results: GSTA1 was the top gene downregulated in high-aldosterone KCNJ5-mutated APAs. GSTA1 was also downregulated in KCNJ5-mutated APAs compared with wild-type KCNJ5 APAs. Accordingly, mutant KCNJ5 decreased GSTA1 messenger RNA and protein expression levels. GSTA1 overexpression suppressed aldosterone secretion whether in wild-type or mutant KCNJ5 H295R cells. Adding ethacrynic acid or silencing of GSTA1 increased aldosterone secretion by increasing reactive oxygen species (ROS), superoxide, H2O2 levels, and Ca2+ influx. The expression of the transcription factors NR4A1, NR4A2, and CAMK1 and intracellular Ca2+ were significantly upregulated by GSTA1 inhibition. The reduced form of NAD phosphate oxidase inhibitor or H2O2 scavenger or blocking calmodulin or calcium channels could significantly reduce aldosterone secretion in GSTA1-inhibited cells.
Conclusions: (1) GSTA1 expression is reversely correlated with aldosterone level in KCNJ5-mutated APAs, (2) GSTA1 regulates aldosterone secretion by ROS and Ca2+ signaling, and (3) KCNJ5 mutation downregulates GSTA1 expression, and overexpression of GSTA1 reverses increased aldosterone in KCNJ5-mutated adrenal cells.

Wang Z, Wu D, Ng CF, et al.
Nuclear receptor profiling in prostatospheroids and castration-resistant prostate cancer.
Endocr Relat Cancer. 2018; 25(1):35-50 [PubMed] Related Publications
Nuclear receptors (NRs), which belong to a superfamily of transcription factors and consist of a total of 48 members in humans, govern the expression of genes involved in a board range of developmental, reproductive, metabolic and immunological programs. Given the significant importance of androgen receptor and a few known NRs in the progression of prostate cancer, we surveyed the expression profiles of the entire NR superfamily in three-dimensional cultured prostatospheroids derived from different prostate cancer cell lines and a tumor xenograft model of castration-resistant prostate cancer VCaP-CRPC by quantitative real-time RT-PCR. Our results revealed that prostatospheroids and castration-relapse VCaP-CRPC xenografts, both contained enriched populations of prostate cancer stem/progenitor-like cells (PCSCs), displayed distinct expression patterns of NRs. Intriguingly, most of these differentially expressed NRs were orphan NRs and showed upregulation. Pairwise analysis identified five orphan NRs (including RORβ, TLX, COUP-TFII, NURR1 and LRH-1) that showed common upregulation in both mRNA and protein levels in the prostatospheroids and castration-relapse VCaP-CRPC xenografts, and overexpression of these orphan NRs could increase cancer stem cell marker expressions and enhance spheroid formation capacity in prostate cancer cells, suggesting that these orphan NRs might perform positive roles in the growth regulation of PCSCs and castration-resistant prostate cancer. Together, our NR expression dataset not only revealed the distinct physiologic status and regulatory roles governed by the networks of specific NRs but also some of these identified orphan NRs could be the potential therapeutic targets for PCSCs or castration-resistant prostate cancer.

Zhu B, Sun L, Luo W, et al.
Activated Notch signaling augments cell growth in hepatocellular carcinoma via up-regulating the nuclear receptor NR4A2.
Oncotarget. 2017; 8(14):23289-23302 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Hepatocellular carcinoma (HCC) is one of the most malignant cancers. Conventional therapies are limited due to the human liver being such a unique organ and easily showing side-effects. The unclear molecular mechanisms are tough challenges for scientists searching for new and effective anti-HCC targeting drugs. We identified that the nuclear receptor NR4A2 is a novel oncogene in HCC progression. In this study, we show that NR4A2 and the notch recceptor Notch1 were expressed highly in primary HCC tissues and immortal HCC cells by using qPCR, western blot and immuno-histochemistry assays. Both genes were observed to stimulate HCC cell proliferation, anti-apoptosis and cell cycle arrest by using cell proliferation assays and FACS assays. We also observed that the four notch receptor subtypes (Notch1-4) displayed different effects on HCC cell growth. The over-expression of Notch1 by transiently transfecting the intracellular domain of Notch1 (ICN1, Notch1 active form) increased the expression of NR4A2, with the knockdown of Notch1 decreasing NR4A2. This indicates that NR4A2 is one of the Notch-mediated downstream genes. Moreover, both NR4A2 and Notch1 suppressed the expression of tumor suppressors p21 and p63. These findings support that Notch1/NR4A2 co-regulate HCC cell functions by playing oncogenic roles and regulating the associated downstream signaling pathways. Novel Notch1/NR4A2-mediated oncogenic signaling may provide us a great opportunity for anti-HCC drug development.

Yang L, Feng S, Yang Y
Identification of transcription factors (TFs) and targets involved in the cholangiocarcinoma (CCA) by integrated analysis.
Cancer Gene Ther. 2016; 23(12):439-445 [PubMed] Related Publications
The present study was designed to investigate the upstream transcription factors (TFs) and the signature genes in cholangiocarcinoma (CCA), providing better clues on the regulatory mechanisms and therapeutic applications. Gene expression data sets of CCA were searched in the Gene Expression Omnibus database for integrated analysis. Functional annotation of differently expressed genes (DEGs) was then conducted and the TFs were identified. Moreover, a global transcriptional regulatory network of TFs-targets was constructed. Integrated analysis of five eligible Gene Expression Omnibus data sets led to a set of 993 DEGs and 48 TFs in CCA. The constructed TFs-targets regulatory network consisted of 697 TF-target interactions between 41 TFs and 436 DEGs. The top 10 TFs covering the most downstream DEGs were NFATC2, SOX10, ARID3A, ZNF263, NR4A2, GATA3, EGR1, PLAG1, STAT3 and FOSL1, which may have important roles in the tumorigenesis of CCA. Supporting the fact that defects of cell-cycle surveillance mechanism were closely related to various cancers, we found that cell cycle was the most significantly enriched pathway. KCNN2 and ADCY6 were involved in the bile secretion. Thus, their aberrant expression may be closely related to the pathogenesis of CCA. Particularly, we found that upregulation of EZH2 in CCA is a powerful potential marker for CCA.

Wallace L, Mehrabi S, Bacanamwo M, et al.
Expression of mitochondrial genes MT-ND1, MT-ND6, MT-CYB, MT-COI, MT-ATP6, and 12S/MT-RNR1 in colorectal adenopolyps.
Tumour Biol. 2016; 37(9):12465-12475 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Despite improvements in treatment strategies, colorectal cancer (CRC) still has high mortality rates. Most CRCs develop from adenopolyps via the adenoma-carcinoma sequence. A mechanism for inhibition of this sequence in individuals with a high risk of developing CRC is urgently needed. Differential studies of mitochondrial (mt) gene expressions in the progressive stages of CRC with villous architecture are warranted to reveal early risk assessments and new targets for chemoprevention of the disease. In the present study, reverse transcription-quantitative PCR (RT-qPCR) was used to determine the relative amount of the transcripts of six mt genes [MT-RNR1, MT-ND1, MT-COI, MT-ATP6, MT-ND6, and MT-CYB (region 648-15887)] which are involved in the normal metabolism of mitochondria. A total of 42 pairs of tissue samples obtained from colorectal adenopolyps, adenocarcinomas, and their corresponding adjacent normal tissues were examined. Additionally, electron transport chain (ETC), complexes I (NADH: ubiquinone oxidoreductase) and III (CoQH2-cytochrome C reductase), and carbonyl protein group contents were analyzed. Results indicate that there were differential expressions of the six mt genes and elevated carbonyl protein contents among the colorectal adenopolyps compared to their paired adjacent normal tissues (p < 0.05). The levels of complexes I and III were higher in tumor tissues relative to adjacent normal tissues. Noticeably, the expression of MT-COI was overexpressed in late colorectal carcinomas among all studied transcripts. Our data suggest that increased expressions in certain mt genes and elevated levels of ROS may potentially play a critical role in the colorectal tumors evolving from adenopolyps to malignant lesions.

Zhou J, Lam B, Neogi SG, et al.
Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues.
Hypertension. 2016; 68(6):1424-1431 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Primary aldosteronism is present in ≈10% of hypertensives. We previously performed a microarray assay on aldosterone-producing adenomas and their paired zona glomerulosa and fasciculata. Confirmation of top genes validated the study design and functional experiments of zona glomerulosa selective genes established the role of the encoded proteins in aldosterone regulation. In this study, we further analyzed our microarray data using AmiGO 2 for gene ontology enrichment and Ingenuity Pathway Analysis to identify potential biological processes and canonical pathways involved in pathological and physiological aldosterone regulation. Genes differentially regulated in aldosterone-producing adenoma and zona glomerulosa were associated with steroid metabolic processes gene ontology terms. Terms related to the Wnt signaling pathway were enriched in zona glomerulosa only. Ingenuity Pathway Analysis showed "NRF2-mediated oxidative stress response pathway" and "LPS (lipopolysaccharide)/IL-1 (interleukin-1)-mediated inhibition of RXR (retinoid X receptor) function" were affected in both aldosterone-producing adenoma and zona glomerulosa with associated genes having up to 21- and 8-fold differences, respectively. Comparing KCNJ5-mutant aldosterone-producing adenoma, zona glomerulosa, and zona fasciculata samples with wild-type samples, 138, 56, and 59 genes were differentially expressed, respectively (fold-change >2; P<0.05). ACSS3, encoding the enzyme that synthesizes acetyl-CoA, was the top gene upregulated in KCNJ5-mutant aldosterone-producing adenoma compared with wild-type. NEFM, a gene highly upregulated in zona glomerulosa, was upregulated in KCNJ5 wild-type aldosterone-producing adenomas. NR4A2, the transcription factor for aldosterone synthase, was highly expressed in zona fasciculata adjacent to a KCNJ5-mutant aldosterone-producing adenoma. Further interrogation of these genes and pathways could potentially provide further insights into the pathology of primary aldosteronism.

Chen J, Qian Z, Li F, et al.
Integrative Analysis of Microarray Data to Reveal Regulation Patterns in the Pathogenesis of Hepatocellular Carcinoma.
Gut Liver. 2017; 11(1):112-120 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Background/Aims: The integration of multiple profiling data and the construction of a transcriptional regulatory network may provide additional insights into the molecular mechanisms of hepatocellular carcinoma (HCC). The present study was conducted to investigate the deregulation of genes and the transcriptional regulatory network in HCC.
Methods: An integrated analysis of HCC gene expression datasets was performed in Gene Expression Omnibus. Functional annotation of the differentially expression genes (DEGs) was conducted. Furthermore, transcription factors (TFs) were identified, and a global transcriptional regulatory network was constructed.
Results: An integrated analysis of eight eligible gene expression profiles of HCC led to 1,835 DEGs. Consistent with the fact that the cell cycle is closely related to various tumors, the functional annotation revealed that genes involved in the cell cycle were significantly enriched. A transcriptional regulatory network was constructed using the 62 TFs, which consisted of 872 TF-target interactions between 56 TFs and 672 DEGs in the context of HCC. The top 10 TFs covering the most downstream DEGs were ZNF354C, NFATC2, ARID3A, BRCA1, ZNF263, FOXD1, GATA3, FOXO3, FOXL1, and NR4A2. This network will appeal to future investigators focusing on the development of HCC.
Conclusions: The transcriptional regulatory network can provide additional information that is valuable in understanding the underlying molecular mechanism in hepatic tumorigenesis.

Beard JA, Tenga A, Hills J, et al.
The orphan nuclear receptor NR4A2 is part of a p53-microRNA-34 network.
Sci Rep. 2016; 6:25108 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Nuclear receptor subfamily 4 group A member 2 (NR4A2) is an orphan nuclear receptor that is over-expressed in cancer and promotes cell proliferation, migration, transformation, and chemoresistance. Increased expression and function of NR4A2 have been attributed to various signaling pathways, but little is known about microRNA (miRNA) regulation of NR4A2 in cancer. To investigate the posttranscriptional regulation of NR4A2, we used a 3' untranslated region (UTR) reporter screen and identified miR-34 as a putative regulator of NR4A2. By using computer predictions, we identified and confirmed an miRNA recognition element in the 3' UTR of NR4A2 that was responsible for miR-34-mediated suppression. We next demonstrated that overexpression of exogenous miR-34 or activation of the p53 pathway, which regulates endogenous miR-34 expression, decreased NR4A2 expression. Consistent with previous reports, overexpression of NR4A2 blocked the induction of p53 target genes, including mir-34a. This was a phenotypic effect, as NR4A2 overexpression could rescue cells from p53-induced inhibition of proliferation. In summary, our results are the first characterization of a cancer-related miRNA capable of regulating NR4A2 and suggest a network and possible feedback mechanism involving p53, miR-34, and NR4A2.

Wang X, Bai Y, Cheng G, et al.
Genomic and proteomic analysis of the inhibition of synthesis and secretion of aldosterone hormone induced by quinocetone in NCI-H295R cells.
Toxicology. 2016; 350-352:1-14 [PubMed] Related Publications
Quinoxaline 1,4-dioxides (QdNOs) are widely used as a kind of antibacterial growth promoter in animal husbandry. The adrenal cortex was found to be one of the main toxic targets of QdNOs, accompanied by a decreased aldosterone level. However, the way in which QdNOs decrease production of the hormone aldosterone is far from clear. To illustrate the mechanism by which QdNOs damage the adrenal cortex and decrease aldosterone hormone levels, the QdNOs were screened to choose the drug with most toxic effects on aldosterone production, and then to reveal the mechanism between the gene and protein profiles in human adrenocortical cells (NCI-H295R cells). The results found that quinocetone (QCT) showed the highest adrenal toxic effect among QdNOs. After exposing H295R cells to 10 and 20μM QCT for 24h, compared with blank cells, the gene and protein expression profiles obtained were analyzed by microarray and MALDI TOF/TOF mass spectrometry, respectively. The results of microarray analysis suggested that ABCG1 and SREBF1, which were involved in the cholesterol biosynthetic and metabolic processes, and CYP17A1, NR4A2 and G6PD, which were related to aldosterone biosynthesis, were important molecular targets. It has been speculated that PKC and ERK pathways might be involved in the reduction of aldosterone production caused by QCT, through enhanced mRNA expression of CYP17A1. Additionally, JNK and p38MAPK signal transduction pathways might participate in apoptosis induced by QCT. Twenty-nine and 32 protein spots were successfully identified when cells were treated with 10 and 20μM QCT, respectively. These identified proteins mainly included material synthesis and energy metabolism-related proteins, transcription/translation processing-related proteins, signal transduction proteins, cytoskeletal proteins, molecular chaperones, proteins related to response to stress, and transport proteins. Further investigations suggested that oxidative stress caused by QCT was exacerbated through disruption of the Keap1/Nrf2/ARE anti-oxidative stress pathway. Taken together, the data demonstrated for the first time that the Keap1/Nrf2/ARE pathway plays a crucial role in adrenal toxicity, and that CYP17A1 was the key switch to reduce the aldosterone production induced by QCT. Furthermore, large numbers of genes and proteins and entry points for research in the inhibition of aldosterone synthesis induced by QCT were offered, which will provide new insight into the adrenal toxicity of QdNOs and help to provide a theoretical foundation for the formulation of safety controls for products obtained from animals and to design new QdNOs with less harmful effects.

Wang J, Yang ZH, Chen H, et al.
Nemo-like kinase as a negative regulator of nuclear receptor Nurr1 gene transcription in prostate cancer.
BMC Cancer. 2016; 16:257 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Nurr1, a member of the orphan receptor family, plays an important role in several types of cancer. Our previous work demonstrated that increased expression of Nurr1 plays a significant role in the initiation and progression of prostate cancer (PCa), though the mechanisms for regulation of Nurr1 expression remain unknown. In this study, we investigated the hypothesis that Nemo-like kinase (NLK) is a key regulator of Nurr1 expression in PCa.
METHODS: Immunohistochemistry and Western blot analysis were used to evaluate levels of NLK and Nurr1 in prostatic tissues and cell lines. The effects of overexpression or knockdown of Nurr1 were evaluated in PCa cells through use of PCR, Western blots and promoter reporter assays. The role of Nurr1 promoter cis element was studied by creation of two mutant Nurr1 promoter luciferase constructs, one with a mutated NF-κB binding site and one with a mutated CREB binding site. In addition, three specific inhibitors were used to investigate the roles of these proteins in transcriptional activation of Nurr1, including BAY 11-7082 (NF-κB inhibitor), KG-501 (CREB inhibitor) and ICG-001 (CREB binding protein, CBP, inhibitor). The function of CBP in NLK-mediated regulation of Nurr1 expression was investigated using immunofluorescence, co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation assays (ChIPs).
RESULTS: NLK expression was inversely correlated with Nurr1 expression in prostate cancer tissues and cell lines. Overexpression of NLK suppressed Nurr1 promoter activity, leading to downregulation of Nurr1 expression. In contrast, knockdown of NLK demonstrated opposite results, leading to upregulation of Nurr1. When compared with the wild-type Nurr1 promoter, mutation of NF-κB- and CREB-binding sites of the Nurr1 promoter region significantly reduced the upregulation of Nurr1 induced by knockdown of NLK in LNCaP cells; treatment with inhibitors of CREB, CBP and NF-κB led to similar results. We also found that NLK directly interacts with CBP, that knockdown of NLK significantly increases the recruitment of CBP to both NF-κB- and CREB-binding sites, and that regulation of NLK on Nurr1 expression is abrogated by knockdown of CBP.
CONCLUSIONS: Our results suggest that NLK inhibits transcriptional activation of Nurr1 gene by impeding CBP's role as a co-activator of NF-κB and CREB in prostate cancer.

Schumacher Y, Aparicio T, Ourabah S, et al.
Dysregulated CRTC1 activity is a novel component of PGE2 signaling that contributes to colon cancer growth.
Oncogene. 2016; 35(20):2602-14 [PubMed] Related Publications
First identified as a dedicated CREB (cAMP response element-binding protein) co-activator, CRTC1 (CREB-regulated transcription co-activator 1) has been widely implicated in various neuronal functions because of its predominant expression in the brain. However, recent evidences converge to indicate that CRTC1 is aberrantly activated in an expanding number of adult malignancies. In this study, we provide strong evidences of enhanced CRTC1 protein content and transcriptional activity in mouse models of sporadic (APC(min/+) mice) or colitis-associated colon cancer azoxymethane/dextran sulfate sodium (AOM/DSS-treated mice), and in human colorectal tumors specimens compared with adjacent normal mucosa. Among signals that could trigger CRTC1 activation during colonic carcinogenesis, we demonstrate that treatment with cyclooxygenase 2 (COX2) inhibitors reduced nuclear CRTC1 active form levels in colonic tumors of APC(min/+) or AOM/DSS mice. In accordance, prostaglandins E2 (PGE2) exposure to human colon cancer cell lines promoted CRTC1 dephosphorylation and parallel nuclear translocation, resulting in enhanced CRTC1 transcriptional activity, through EP1 and EP2 receptors signaling and consecutive calcineurin and protein kinase A activation. In vitro CRTC1 loss of function in colon cancer cell lines was associated with reduced viability and cell division rate as well as enhanced chemotherapy-induced apoptosis on PGE2 treatment. Conversely, CRTC1 stable overexpression significantly increased colonic xenografts tumor growth, therefore demonstrating the role of CRTC1 signaling in colon cancer progression. Identification of the transcriptional program triggered by enhanced CRTC1 expression during colonic carcinogenesis, revealed some notable pro-tumorigenic CRTC1 target genes including NR4A2, COX2, amphiregulin (AREG) and IL-6. Finally, we demonstrate that COX2, AREG and IL-6 promoter activities triggered by CRTC1 are dependent on functional AP1 and CREB transcriptional partners. Overall, our study establishes CRTC1 as new mediator of PGE2 signaling, unravels the importance of its dysregulation in colon cancer and strengthens its use as a bona fide cancer marker.

Guo J, Zu G, Zhou T, et al.
Clinicopathological significance of orphan nuclear receptor Nurr1 expression in gastric cancer.
Clin Transl Oncol. 2015; 17(10):788-94 [PubMed] Related Publications
BACKGROUND: Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related deaths worldwide. Gastric cancer is characterized by high levels of invasion and metastasis. Increasing attention is being focused on discovering molecular markers for the diagnosis of gastric cancer and for predicting its prognosis. The objective of the present study was to evaluate Nurr1 expression in gastric cancer and to assess its correlation with clinicopathological parameters and prognosis in gastric cancer patients.
METHODS: Tissue samples were obtained from 120 gastric cancer patients. We investigated Nurr1 expression in human normal and gastric cancer tissues using real-time reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. We determined the association between Nurr1 and recurrence, prognosis and patient clinicopathological parameters. Univariate and multivariate survival analyses with a Cox's proportional hazards regression model were used to identify independent factors related to recurrence and prognosis.
RESULTS: The immunohistochemical, qRT-PCR and western blot analyses revealed that Nurr1 expression was increased in gastric cancer tissues compared with normal gastric tissue (P < 0.05). Nurr1 expression was significantly correlated with the tumor size, depth of tumor invasion, lymph node metastasis, recurrence, and distant metastasis of gastric cancer (P < 0.05). Moreover, Nurr1-high patients also exhibited poorer overall survival (OS) and disease-free survival compared with Nurr1-low patients (P < 0.01). The univariate and multivariate survival analyses suggested that Nurr1 expression (P = 0.011), histology (P = 0.018), depth of tumor invasion (P = 0.037), and presence of lymph node metastasis (P = 0.031) were independent prognostic factors for recurrence. In addition, Nurr1 expression (P = 0.007), depth of tumor invasion (P = 0.014), lymph node metastasis (P = 0.044), distant metastasis (P = 0.023), and recurrence (P = 0.011) were independent prognostic factors of OS in gastric cancer patients.
CONCLUSIONS: The Nurr1 protein may be useful as a marker of recurrence, metastasis, and poor prognosis following curative resection in patients with gastric cancer.

Bai R, Weng C, Dong H, et al.
MicroRNA-409-3p suppresses colorectal cancer invasion and metastasis partly by targeting GAB1 expression.
Int J Cancer. 2015; 137(10):2310-22 [PubMed] Related Publications
Colorectal cancer (CRC) is one of the most common cancers worldwide and its metastasis accounts for the majority of deaths. However, the molecular mechanisms underlying CRC progression are not well characterized. In this study, we identified miR-409-3p as a tumor suppressor of CRC. MiR-409-3p expression was significantly downregulated in CRC tissue compared to adjacent non-tumor tissue, and reduced miR-409-3p expression was correlated with CRC metastasis. In vitro and in vivo studies revealed that miR-409-3p negatively regulated CRC metastatic capacities, including suppressing cancer cell migration, invasion and metastasis. To explore the mechanism of action of miR-409-3p, we adopted a pathway and pathophysiological event-based target screening and validation approach, and found nine known metastasis-related genes as potential targets. The 3'-UTR binding assays between the candidates and miR-409-3p suggested that only GAB1, NR4A2 and LMO4 were directly regulated by the miRNA. However, endogenous expression analysis revealed that only GAB1 was modulated by miR-409-3p in CRC cells at both the mRNA and protein levels. Furthermore, we provided evidence to conclude that GAB1 was partially responsible for miR-409-3p-mediated metastasis. Taken together, our data demonstrate that miR-409-3p is a metastatic suppressor, and post-transcriptional inhibition of the oncoprotein GAB1 is one of the mechanisms of action of this miRNA. Our finding suggests miR-409-3p might be a novel target for CRC metastasis treatment.

Safe S, Jin UH, Morpurgo B, et al.
Nuclear receptor 4A (NR4A) family - orphans no more.
J Steroid Biochem Mol Biol. 2016; 157:48-60 [PubMed] Free Access to Full Article Related Publications
The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurological functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions. Although endogenous ligands for NR4A receptors have not been identified, there is increasing evidence that structurally-diverse synthetic molecules can directly interact with the ligand binding domain of NR4A1 and act as agonists or antagonists, and ligands for NR4A2 and NR4A3 have also been identified. Since NR4A receptors are key factors in multiple diseases, there are opportunities for the future development of NR4A ligands for clinical applications in treating multiple health problems including metabolic, neurologic and cardiovascular diseases, other inflammatory conditions, and cancer.

Rusan M, Li YY, Hammerman PS
Genomic landscape of human papillomavirus-associated cancers.
Clin Cancer Res. 2015; 21(9):2009-19 [PubMed] Free Access to Full Article Related Publications
Recent next-generation sequencing studies have generated a comprehensive overview of the genomic landscape of human papillomavirus (HPV)-associated cancers. This review summarizes these findings to provide insight into the tumor biology of these cancers and potential therapeutic opportunities for HPV-driven malignancies. In addition to the tumorigenic properties of the HPV oncoproteins, integration of HPV DNA into the host genome is suggested to be a driver of the neoplastic process. Integration may confer a growth and survival advantage via enhanced expression of viral oncoproteins, alteration of critical cellular genes, and changes in global promoter methylation and transcription. Alteration of cellular genes may lead to loss of function of tumor suppressor genes, enhanced oncogene expression, loss of function of DNA repair genes, or other vital cellular functions. Recurrent integrations in RAD51B, NR4A2, and TP63, leading to aberrant forms of these proteins, are observed in both HPV-positive head and neck squamous cell carcinoma (HNSCC) and cervical carcinoma. Additional genomic alterations, independent of integration events, include recurrent PIK3CA mutations (and aberrations in other members of the PI3K pathway), alterations in receptor tyrosine kinases (primarily FGFR2 and FGFR3 in HPV-positive HNSCC, and ERBB2 in cervical squamous cell carcinoma), and genes in pathways related to squamous cell differentiation and immune responses. A number of the alterations identified are potentially targetable, which may lead to advances in the treatment of HPV-associated cancers.

Marrelli M, Paduano F, Tatullo M
Human periapical cyst-mesenchymal stem cells differentiate into neuronal cells.
J Dent Res. 2015; 94(6):843-52 [PubMed] Related Publications
It was recently reported that human periapical cysts (hPCys), a commonly occurring odontogenic cystic lesion of inflammatory origin, contain mesenchymal stem cells (MSCs) with the capacity for self-renewal and multilineage differentiation. In this study, periapical inflammatory cysts were compared with dental pulp to determine whether this tissue may be an alternative accessible tissue source of MSCs that retain the potential for neurogenic differentiation. Flow cytometry and immunofluorescence analysis indicated that hPCy-MSCs and dental pulp stem cells spontaneously expressed the neuron-specific protein β-III tubulin and the neural stem-/astrocyte-specific protein glial fibrillary acidic protein (GFAP) in their basal state before differentiation occurs. Furthermore, undifferentiated hPCy-MSCs showed a higher expression of transcripts for neuronal markers (β-III tubulin, NF-M, MAP2) and neural-related transcription factors (MSX-1, Foxa2, En-1) as compared with dental pulp stem cells. After exposure to neurogenic differentiation conditions (neural media containing epidermal growth factor [EGF], basic fibroblast growth factor [bFGF], and retinoic acid), the hPCy-MSCs showed enhanced expression of β-III tubulin and GFAP proteins, as well as increased expression of neurofilaments medium, neurofilaments heavy, and neuron-specific enolase at the transcript level. In addition, neurally differentiated hPCy-MSCs showed upregulated expression of the neural transcription factors Pitx3, Foxa2, Nurr1, and the dopamine-related genes tyrosine hydroxylase and dopamine transporter. The present study demonstrated for the first time that hPCy-MSCs have a predisposition toward the neural phenotype that is increased when exposed to neural differentiation cues, based on upregulation of a comprehensive set of proteins and genes that define neuronal cells. In conclusion, these results provide evidence that hPCy-MSCs might be another optimal source of neural/glial cells for cell-based therapies to treat neurologic diseases.

Roshan-Moniri M, Hsing M, Butler MS, et al.
Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers.
Cancer Treat Rev. 2014; 40(10):1137-52 [PubMed] Related Publications
Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B-like receptors, and ‘‘dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1’’ (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers.

Wenzl K, Troppan K, Neumeister P, Deutsch AJ
The nuclear orphan receptor NR4A1 and NR4A3 as tumor suppressors in hematologic neoplasms.
Curr Drug Targets. 2015; 16(1):38-46 [PubMed] Related Publications
NR4A1 (Nur77) belongs together with NR4A2 (Nurr1) and NR4A3 (NOR-1) to the nuclear orphan receptors of the NR4A-family. Their activation is generally short lived, the cellular outcome is a stimulus- and cell context-dependent differential activation of NR4A target genes that regulate cell cycle, apoptosis, inflammation, atherogenesis, metabolism, DNA repair and tumorigenesis. NR4A1 and NR4A3 were identified to function as tumor suppressors in acute myeloid leukemia (AML). Deletion of both nuclear receptors led to rapid development of AML in mice. Loss of NR4A1 and NR4A3 was a common feature in human AML patients. Additionally, NR4A1 and NR4A3 hypoallelic mice - mice with a reduced NR4A1 and NR4A3 expression - develop a chronic myeloid malignancy that recapitulates the pathological features of myelodysplastic/ myeloproliferative neoplasms with progression to AML in rare cases. Recently, a reduced NR4A1 and NR4A3 expression was described in aggressive lymphomas and low NR4A1 expression was associated with poor overall survival. Overexpression of NR4A1 in aggressive lymphoma cells led to induction of apoptosis and abrogated tumor growth in a xenograft mouse model. Recently, it was shown that NR4A inducing agents or NR4A agonist possess/induce apoptotic effects in AML and lymphoma cells. Due to this fact and the growing number of NR4A1 and NR4A3 inducing agents and NR4A agonists, both receptors represent new targets for anti tumor therapy.

Ranhotra HS
The NR4A orphan nuclear receptors: mediators in metabolism and diseases.
J Recept Signal Transduct Res. 2015; 35(2):184-8 [PubMed] Related Publications
The NR4A subfamily is orphan nuclear receptors that belong to the larger nuclear receptors (NRs) superfamily of eukaryotic transcription factors. The NR4A subfamily includes three members, namely Nur77 (NR4A1), Nurr1 (NR4A2) and Nor1 (NR4A3) which are gene regulators and participate in diverse biological functions. Though the ligands for these receptors are presently unidentified, they are thought to be constitutively active. NR4A acts as molecular switches in gene regulation and their action is increasingly seen to be modulated by complex network of cellular signaling pathways. Members of the NR4A are expressed in tissue-specific fashion which indicates their selective control of various biological processes. Data reveal a host of functions governed by the NR4A subfamily members including general metabolism, immunity, cellular stress, memory, insulin sensitivity and cardiac homeostasis by regulating specific target genes whose products participates in such processes. Moreover, these receptors have a role in the onset and progression of various diseases such as various types of cancer, inflammation, atherosclerosis and obesity. In this review, a concise overview of the current understanding of the important metabolic roles governed by NR4A members including their participation in a number of diseases shall be provided.

Yin K, Sturm RA, Smith AG
MC1R and NR4A receptors in cellular stress and DNA repair: implications for UVR protection.
Exp Dermatol. 2014; 23(7):449-52 [PubMed] Related Publications
Ultraviolet radiation (UVR) is the most common mutagen that melanocytes are exposed to. UVR causes a diverse range of DNA photolesions contributing to genome instability and promotes melanoma and non-melanoma development. Melanocytes are pigment-producing cells that synthesise the photoprotective melanins when the melanocortin-1 receptor (MC1R) is activated. MC1R is a G-protein-coupled receptor expressed predominantly in melanocytes. Its signalling pathway has been directly linked to melanogenesis, enhanced cytoprotection against UV damage and augmented DNA repair response. Interestingly, previous studies have revealed that MC1R signalling induces the transcription of the NR4A subfamily of orphan nuclear receptors in response to UV. In line with this, studies have also observed that NR4A receptors are recruited to distinct nuclear foci in response to cellular stress, independent of their transcriptional roles. Here, we review the regulated expression of NR4A2 and its potential roles upon cellular stress conditions. Current work in developing synthetic NR4A2 agonists further provides exciting avenues for exploring the potential role of NR4A2 as an antiskin cancer drug target.

Safe S, Jin UH, Hedrick E, et al.
Minireview: role of orphan nuclear receptors in cancer and potential as drug targets.
Mol Endocrinol. 2014; 28(2):157-72 [PubMed] Free Access to Full Article Related Publications
The nuclear orphan receptors for which endogenous ligands have not been identified include nuclear receptor (NR)0B1 (adrenal hypoplasia congenita critical region on chromosome X gene), NR0B2 (small heterodimer partner), NR1D1/2 (Rev-Erbα/β), NR2C1 (testicular receptor 2), NR2C2 (testicular receptor 4), NR2E1 (tailless), NR2E3 (photoreceptor-specific NR [PNR]), NR2F1 chicken ovalbumin upstream promoter transcription factor 1 (COUP-TFI), NR2F2 (COUP-TFII), NR2F6 (v-erbA-related protein), NR4A1 (Nur77), NR4A2 (Nurr1), NR4A3 (Nor1), and NR6A1 (GCNF). These receptors play essential roles in development, cellular homeostasis, and disease including cancer where over- or underexpression of some receptors has prognostic significance for patient survival. Results of receptor knockdown or overexpression in vivo and in cancer cell lines demonstrate that orphan receptors exhibit tumor-specific pro-oncogenic or tumor suppressor-like activity. For example, COUP-TFII expression is both a positive (ovarian) and negative (prostate and breast) prognostic factor for cancer patients; in contrast, the prognostic activity of adrenal hypoplasia congenita critical region on chromosome X gene for the same tumors is the inverse of COUP-TFII. Functional studies show that Nur77 is tumor suppressor like in acute leukemia, whereas silencing Nur77 in pancreatic, colon, lung, lymphoma, melanoma, cervical, ovarian, gastric, and some breast cancer cell lines induces one or more of several responses including growth inhibition and decreased survival, migration, and invasion. Although endogenous ligands for the orphan receptors have not been identified, there is increasing evidence that different structural classes of compounds activate, inactivate, and directly bind several orphan receptors. Thus, the screening and development of selective orphan receptor modulators will have important clinical applications as novel mechanism-based agents for treating cancer patients overexpressing one or more orphan receptors and also for combined drug therapies.

Johannessen CM, Johnson LA, Piccioni F, et al.
A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.
Nature. 2013; 504(7478):138-42 [PubMed] Free Access to Full Article Related Publications
Malignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics.

Berthon A, Drelon C, Ragazzon B, et al.
WNT/β-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production.
Hum Mol Genet. 2014; 23(4):889-905 [PubMed] Related Publications
Primary aldosteronism (PA) is the main cause of secondary hypertension, resulting from adrenal aldosterone-producing adenomas (APA) or bilateral hyperplasia. Here, we show that constitutive activation of WNT/β-catenin signalling is the most frequent molecular alteration found in 70% of APA. We provide evidence that decreased expression of the WNT inhibitor SFRP2 may be contributing to deregulated WNT signalling and APA development in patients. This is supported by the demonstration that mice with genetic ablation of Sfrp2 have increased aldosterone production and ectopic differentiation of zona glomerulosa cells. We further show that β-catenin plays an essential role in the control of basal and Angiotensin II-induced aldosterone secretion, by activating AT1R, CYP21 and CYP11B2 transcription. This relies on both LEF/TCF-dependent activation of AT1R and CYP21 regulatory regions and indirect activation of CYP21 and CYP11B2 promoters, through increased expression of the nuclear receptors NURR1 and NUR77. Altogether, these data show that aberrant WNT/β-catenin activation is associated with APA development and suggest that WNT pathway may be a good therapeutic target in PA.

Misund K, Selvik LK, Rao S, et al.
NR4A2 is regulated by gastrin and influences cellular responses of gastric adenocarcinoma cells.
PLoS One. 2013; 8(9):e76234 [PubMed] Free Access to Full Article Related Publications
The peptide hormone gastrin is known to play a role in differentiation, growth and apoptosis of cells in the gastric mucosa. In this study we demonstrate that gastrin induces Nuclear Receptor 4A2 (NR4A2) expression in the adenocarcinoma cell lines AR42J and AGS-GR, which both possess the gastrin/CCK2 receptor. In vivo, NR4A2 is strongly expressed in the gastrin responsive neuroendocrine ECL cells in normal mucosa, whereas gastric adenocarcinoma tissue reveals a more diffuse and variable expression in tumor cells. We show that NR4A2 is a primary early transient gastrin induced gene in adenocarcinoma cell lines, and that NR4A2 expression is negatively regulated by inducible cAMP early repressor (ICER) and zinc finger protein 36, C3H1 type-like 1 (Zfp36l1), suggesting that these gastrin regulated proteins exert a negative feedback control of NR4A2 activated responses. FRAP analyses indicate that gastrin also modifies the nucleus-cytosol shuttling of NR4A2, with more NR4A2 localized to cytoplasm upon gastrin treatment. Knock-down experiments with siRNA targeting NR4A2 increase migration of gastrin treated adenocarcinoma AGS-GR cells, while ectopically expressed NR4A2 increases apoptosis and hampers gastrin induced invasion, indicating a tumor suppressor function of NR4A2. Collectively, our results uncover a role of NR4A2 in gastric adenocarcinoma cells, and suggest that both the level and the localization of NR4A2 protein are of importance regarding the cellular responses of these cells.

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