ArticleScientific reports2016
Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 48 citations in OpenAlex.
- Microbial dysbiosis drives colorectal carcinogenesis via integrated inflammatory, metabolic, and biofilm pathways.Frontiers in microbiology · 2026Review
- NR4A3high mast cells promote ovarian cancer metastasis by reprogramming tumor-associated macrophages via JAK2/STAT6 signaling.Translational oncology · 2025Article
- NNMT-mediated NOncogene · 2025Article
- Investigation methylation status of tumor suppressor geneMolecular biology research communications · 2025Article
- A pan-cancer analysis unveiling the function of NR4A family genes in tumor immune microenvironment, prognosis, and drug response.Genes & genomics · 2024Article
- Potential Roles of Nr4a3-Mediated Inflammation in Immunological and Neurological Diseases.Molecular neurobiology · 2024Review
- NR4A3 inhibits the tumor progression of hepatocellular carcinoma by inducing cell cycle G0/G1 phase arrest and upregulation of CDKN2AIP expression.International journal of biological sciences · 2024Article
- The possibilities of LOXL4 as a prognostic marker for carcinomas.Amino acids · 2023Review
- Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis.Annals of hematology · 2022Article
- Matriptase-2/NR4A3 axis switches TGF-β action toward suppression of prostate cancer cell invasion, tumor growth, and metastasis.Oncogene · 2022Article
- GSK3B Overexpression Alleviates Posttraumatic Osteoarthritis in Mice by Promoting DNMT1-Mediated Hypermethylation of NR4A3 Promoter.Disease markers · 2022Article
- The TNF-Alpha Inducing Protein is Associated With Gastric Inflammation and Hyperplasia in a Murine Model ofFrontiers in pharmacology · 2022Article
- JAK/STAT Signaling: Molecular Targets, Therapeutic Opportunities, and Limitations of Targeted Inhibitions in Solid Malignancies.Frontiers in pharmacology · 2022Review
- Purinergic P2Y2 and P2X4 Receptors Are Involved in the Epithelial-Mesenchymal Transition and Metastatic Potential of Gastric Cancer Derived Cell Lines.Pharmaceutics · 2021Article
- Article
- Identification of circRNA-miRNA-mRNA networks contributes to explore underlying pathogenesis and therapy strategy of gastric cancer.Journal of translational medicine · 2021Article
- HDAC1 and 2 regulate endothelial VCAM-1 expression and atherogenesis by suppressing methylation of theTheranostics · 2021Article
- Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer.Frontiers in oncology · 2021Article
- Methylomic analysis identifies C11orf87 as a novel epigenetic biomarker for GI cancers.PloS one · 2021Article
- Mechanisms of JAK-STAT signaling pathway mediated by CXCL8 gene silencing on epithelial-mesenchymal transition of human cutaneous melanoma cells.Oncology letters · 2020Article
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Authors and funding
18 authors at 8 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
While aberrant JAK/STAT signaling is crucial to the development of gastric cancer (GC), its effects on epigenetic alterations of its transcriptional targets remains unclear. In this study, by expression microarrays coupled with bioinformatic analyses, we identified a putative STAT3 target gene, NR4A3 that was downregulated in MKN28 GC daughter cells overexpressing a constitutively activated STAT3 mutant (S16), as compared to an empty vector control (C9). Bisulphite pyrosequencing and demethylation treatment showed that NR4A3 was epigenetically silenced by promoter DNA methylation in S16 and other GC cell lines including AGS cells, showing constitutive activation of STAT3. Subsequent experiments revealed that NR4A3 promoter binding by STAT3 might repress its transcription. Long-term depletion of STAT3 derepressed NR4A3 expression, by promoter demethylation, in AGS GC cells. NR4A3 re-expression in GC cell lines sensitized the cells to cisplatin, and inhibited tumor growth in vitro and in vivo, in an animal model. Clinically, GC patients with high NR4A3 methylation, or lower NR4A3 protein expression, had significantly shorter overall survival. Intriguingly, STAT3 activation significantly associated only with NR4A3 methylation in low-stage patient samples. Taken together, aberrant JAK/STAT3 signaling epigenetically silences a potential tumor suppressor, NR4A3, in gastric cancer, plausibly representing a reliable biomarker for gastric cancer prognosis.
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