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

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Resende, C (Author) Other; Regalo, G (Author) Other; Duraes, C (Author) Other; Pinto, MT (Author) Other; Wen, XG (Author) Other; Figueiredo C (Author) FMUP; Carneiro F (Author) FMUP; Machado JC (Author) FMUP

Journal

Title: Gastric Cancer

Vol. 19

Pages: 74-84

ISSN: 1436-3291

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 19 Citations

Scopus - 18 Citations

Other information

Authenticus ID: P-00G-1WM

DOI: 10.1007/s10120-014-0448-x

Abstract (EN): 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 IL1I' signalling, as seen in the context of Helicobacter pylori infection, could be linked to gastric carcinogenesis by modulating the behaviour of gastric epithelial cells. The effect of IL1B was assessed by studying the expression and activation status of the IL1I'-activated transcription factors C/EBP beta and CREB in GC cell lines. Interaction between CREB and C/EBP beta was explored through interference RNA, chromatin immunoprecipitation and chemical inhibition. CREB and C/EBP beta 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. We found that IL1B regulates the expression/activation status of both C/EBP beta 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/EBP beta expression (P < 0.05). Finally, we demonstrated both in vitro and in vivo that CREB can mediate IL1B-induced GC cell proliferation. 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/EBP beta, 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11