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.
Highlights
Gastric cancer (GC) is the third leading cause of cancer death worldwide[1]
Other studies have demonstrated that STAT3 activation is more prominent in gastric cancer (GC) patients infected with cytotoxin-associated gene A (CagA)-positive H. pylori[20], the exact role of Janus kinase (JAK)/STAT signaling in GC is not fully understood
Several studies have already demonstrated that activation of JAK/STAT signaling is crucial to gastric carcinogenesis with particular regard to H. pylori-infected tissues[8,17,42]; its role in epigenetic silencing of its target genes has not been fully explored
Summary
Gastric cancer (GC) is the third leading cause of cancer death worldwide[1]. About 90% of GCs are adenocarcinomas, which can be classified into poorly differentiated diffuse, well-differentiated intestinal, and mixed types[2]. Both S16 and AGS cells showed MMP7 upregulation, compared to C9 control and MKN28 GC cells. With increased cytokine expression in interleukin-6, (IL-6), and robust inflammatory response, in gastric cancer[12,13], suggesting that activation of IL-6-JAK/STAT3 signaling pathways may be crucial for GC development. Other studies have demonstrated that STAT3 activation is more prominent in GC patients infected with CagA-positive H. pylori[20], the exact role of JAK/STAT signaling in GC is not fully understood. The mechanism of how aberrant promoter methylation arises is not fully understood
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