209: STAT3-driven regulation of microRNAs during gastric inflammation-associated tumourigenesis

Abstract

Hyperactivation of the latent transcription factor signal transducer and activator of transcription (STAT)3 is frequently observed in inflammation-associated gastric cancer. However the full spectrum of downstream gene networks modulated by STAT3 during the pathogenesis of gastric tumourigenesis remains ill-defined. The gp130 F / F gastric cancer mouse model which recapitulates the hyperactive STAT3 signaling and tumor progression observed in human disease was therefore employed to identify novel STAT3-regulated microRNAs (miRNAs) associated with the onset of gastric tumours. Using a miRNA array approach coupled with miRNA real-time quantitative PCR validation, we identified that 2 miRNAs (miR-146b and miR-429) are consistently up in stomach tissue from gp130 F / F mice at 4 weeks (prior to tumour initiation) and 3 months (established tumour formation) of age compared to age-matched wild type mice. Consistent with our previous demonstration that interleukin (IL)-11/STAT3 signaling plays a causal role during gastric tumourigenesis in gp130 F / F mice, normalization of gastric STAT3 activation and IL-11 expression in gp130 F / F mice lacking the IL-11 ligand-binding receptor subunit (IL-11Ra) also normalized the expression of these miRNAs. We also found that in response to IL-11 treatment of wild-type mice, miR-146b and miR-429 are significantly increased along with STAT3 activation. Furthermore, these 2 miRs are upregulated in human intestinal-type gastric cancer biopsies characterized by increased STAT3 signaling. Collectively, our data reveal 2 novel STAT3-regulated miRNAs in gastric tumourigenesis, and therefore suggest that the regulation of specific miRNAs may represent an additional mechanism by which STAT3 promotes oncogenesis in the stomach.