Interleukin-1B signalling leads to increased survival of gastric carcinoma cells through a CREB-C/EBPβ-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 IL1Β 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 IL1Β-activated transcription factors C/EBPβ and CREB in GC cell lines. Interaction between CREB and C/EBPβ was explored through interference RNA, chromatin immunoprecipitation and chemical inhibition. CREB and C/EBPβ 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/EBPβ 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/EBPβ 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. IL1B is able to increase the expression/activation status of CREB and its target gene C/EBPβ, 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.
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology (Ipatimup), University of Porto, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Porto, Portugal.
Carlos
C
Resende
Institute of Molecular Pathology and Immunology (Ipatimup), University of Porto, Porto, Portugal.
Gonçalo
G
Regalo
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology (Ipatimup), University of Porto, Porto, Portugal.
Cecília
C
Durães
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology (Ipatimup), University of Porto, Porto, Portugal.
Marta Teixeira
MT
Pinto
Serviço de Anatomia Patológica, Centro Hospitalar Vila Nova de Gaia/Espinho, Gaia, Portugal.
Xiaogang
X
Wen
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology (Ipatimup), University of Porto, Porto, Portugal.|Faculty of Medicine, University of Porto, Porto, Portugal.
Ceu
C
Figueiredo
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology (Ipatimup), University of Porto, Porto, Portugal.|Faculty of Medicine, University of Porto, Porto, Portugal.
Fátima
F
Carneiro
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. josem@ipatimup.pt.|Institute of Molecular Pathology and Immunology (Ipatimup), University of Porto, Porto, Portugal. josem@ipatimup.pt.|Faculty of Medicine, University of Porto, Porto, Portugal. josem@ipatimup.pt.
José C
JC
Machado
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D016481:Helicobacter Infections / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology*
D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D053583:Interleukin-1beta
Gastric cancer; Genetic susceptibility; Helicobacter pylori; IL1B; Inflammation