Interleukin-1B signalling leads to increased survival of gastric carcinoma cells through a CREB-C/EBPb-associated mechanism

Background Polymorphisms in inflammation-related genes have been associated with a risk of gastric carcinoma (GC). However, the biological mechanisms underlying these associations are still elusive. Our objective was to determine whether chronic inflammation-associated IL1B signalling, as seen in the context of Helicobacter pylori infection, could be linked to gastric carcinogenesis by modulating the behaviour of gastric epithelial cells. Methods The effect of IL1B was assessed by studying the expression and activation status of the IL1B-activated transcription factors C/EBPb and CREB in GC cell lines. Interaction between CREB and C/EBPb was explored through interference RNA, chromatin immunoprecipitation and chemical inhibition. CREB and C/EBPb expression was analysed in 66 samples of primary GC and in normal gastric mucosa. GC cell growth was analysed in vitro by BrdU incorporation and in vivo employing a chicken embryo chorioallantoic membrane model. Results We found that IL1B regulates the expression/ activation status of both C/EBPb and CREB in GC cells through an ERK1/2-dependent mechanism. Our results show that CREB is a direct transactivator of CEBPB, acting as an upstream effector in this regulatory mechanism. Furthermore, we found CREB to be overexpressed in 94 % of GC samples and significantly associated with C/EBPb expression (P\0.05). Finally, we demonstrated both in vitro and in vivo that CREB can mediate IL1B-induced GC cell proliferation. Conclusions Our results support the hypothesis that the effect of chronic inflammation on gastric carcinogenesis, as seen in the context of genetically susceptible individuals infected with Helicobacter pylori, includes the modulation of signalling pathways that regulate survival mechanisms in epithelial cells. Summary IL1B is able to increase the expression/activation status of CREB and its target gene C/EBPb, which are mandatory for GC cell survival. Our results may help inform new strategies for the prevention and treatment of GC, including the control of chronic inflammation.