Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer
| Autor: | Michael W.Y. Chan, Chung-Min Yeh, Cheng-Yu Lin, Enders K.W. Ng, Claudia Dittner, Li-Han Zeng, Hsiao-Wen Wang, Jian-Liang Chou, Alfred S. L. Cheng, Jiayuh Lin, Liang-Yu Chang, Kun-Tu Yeh, Sheng-Yu Chuang, Shu-Hui Lin, Jora M. J. Lin, Shu-Fen Wu, Hsiao-Yen Hsieh, Yao-Ting Huang |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
STAT3 Transcription Factor Receptors Steroid Biology Article Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Stomach Neoplasms Cell Line Tumor Gene silencing Humans Epigenetics Gene Silencing STAT3 Promoter Regions Genetic Janus Kinases Multidisciplinary Receptors Thyroid Hormone Promoter Methylation DNA Methylation Prognosis Molecular biology DNA-Binding Proteins 030104 developmental biology Cell culture 030220 oncology & carcinogenesis DNA methylation Cancer research biology.protein Signal transduction Signal Transduction |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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