STAT3-driven regulation of microRNAs during gastric inflammation-associated tumourigenesis — ASN Events

STAT3-driven regulation of microRNAs during gastric inflammation-associated tumourigenesis (#209)

Liang Yu 1 , Anna Tsykin 2 , Gregory Goodall 2 , Brendan Jenkins 1
  1. Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute, Melbourne, VIC, Australia
  2. Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia

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 gp130F/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 gp130F/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 gp130F/F mice, normalization of gastric STAT3 activation and IL-11 expression in gp130F/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.