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

Abstract

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.

Expression Profiling of a Human Thyroid Cell Line Stably Expressing the BRAFV600E Mutation

“…In human thyrocytes, IL-1β alters the expression and localization of junction proteins (27). IL-1β induces the activation of cAMP responsive element-binding protein (CREB) through ERK1/2 signaling, and this mechanism was associated with poor prognosis in gastric carcinoma, non-small cell lung cancer, and breast cancer patients in previous reports (28)(29)(30).…”

Helicobacter pylori controls NLRP3 expression by regulating hsa-miR-223-3p and IL-10 in cultured and primary human immune cells

“…13 In addition, IL-1b was reported to directly induce proliferation of gastric carcinoma cells. 14 Therefore, the production of IL-1b is implicated as one of the key host factors for H. pylori-associated gastric cancer progression.…”

Inflammasomes in Inflammation-Induced Cancer

“…Combined with other cytokines like TNF-α, it leads to loss of parietal cells, subsequent gastric atrophy, metaplasia, and eventually gastric cancer (151, 152). What’s more, IL-1β can reinforce gastric carcinoma growth through ERK1/2 kinase signaling, as the result of the activation of CREB and C/EBPβ (153). …”