Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer

• DOI: 10.1038/srep31690
• Publication Date: 2016-08-16T09:37:39Z
• Authors: Chung-Min Yeh; Liang-Yu Chang; Shu-Hui Lin; Jian-Liang Chou; Hsiao-Yen Hsieh; Li-Han Zeng; Sheng-Yu Chuang; Hsiao-Wen Wang; Claudia Dittner; Cheng-Yu Lin; Jora M. J. Lin; Yao-Ting Huang; Enders K. W. Ng; Alfred S. L. Cheng; Shu-Fen Wu; Jiayuh Lin; Kun-Tu Yeh; Michael W. Y. Chan
• Keywords: Bisulfite sequencing

Abstract While aberrant JAK/STAT signaling is crucial to the development of gastric cancer (GC), its effects on epigenetic alterations 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 constitutively activated mutant (S16), as compared an empty vector control (C9). Bisulphite pyrosequencing and demethylation treatment showed epigenetically silenced promoter DNA methylation S16 other cell lines including AGS cells, showing constitutive activation STAT3. Subsequent experiments revealed binding might repress transcription. Long-term depletion derepressed expression, demethylation, cells. re-expression sensitized cisplatin inhibited tumor growth vitro vivo , animal model. Clinically, patients high methylation, or lower protein had significantly shorter overall survival. Intriguingly, associated only low-stage patient samples. Taken together, JAK/STAT3 silences potential suppressor, NR4A3, cancer, plausibly representing reliable biomarker for prognosis.