C/EBPbeta is over‐expressed in gastric carcinogenesis and is associated with COX‐2 expression

Regalo, Gonçalo; Canedo, Paulo; Suriano, Gianpaolo; Resende, Carlos; Campos, ML; Oliveira, Maria José; Figueiredo, Céu; Rodrigues-Pereira, Pedro; Blin, Nikolaus; Seruca, Raquel; Carneiro, Fátima; Machado, José Carlos

doi:10.1002/path.2063

Cited by 31 publications

(23 citation statements)

References 19 publications

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“…This would be in accordance with the observed pattern of overexpression of both proteins in the majority of the GC cases included in the present study. These results are also in keeping with our previous demonstration that C/EBPb is overexpressed in pre-malignant lesions and in GC, suggesting that this protein might facilitate the transformation of gastric epithelial cells by inducing the expression of COX-2 [23] and by inhibiting the expression of the putative gastric tumor suppressor gene TFF1 [24,25].…”

Section: Discussionsupporting

confidence: 80%

“…One of the IL1B-activated transcription factors is CCAAT/enhancer-binding protein beta (C/EBPb) [22]. We previously reported that C/EBPb is overexpressed in pre-malignant lesions and in GC, suggesting that this protein may facilitate gastric carcinogenesis by inducing the expression of COX-2 [23]. Furthermore, C/EBPb expression in GC was significantly associated with loss of expression of the putative gastric tumour-suppressor TFF1 [24,25].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…Activation of C/EBPβ is crucial for the initial induction of COX-2 by growth factors, tumor promoters, cytokines and other inflammatory mediators in various types of cells (43,44). Further study revealed that C/EBPβ and COX-2 showed overlapping overexpression in gastric carcinomas and that C/EBPβ has the potential to mediate gastric carcinogenesis via the regulation of COX-2 expression (24). In human prostate tissues, the expression of C/EBPβ and COX-2 was highly correlated and was involved in chronic inflammation and prostate cancer development (45).…”

Section: Discussionmentioning

confidence: 99%

“…C/EBPβ is one of the regulators implicated in COX-2 expression (23), and the two proteins are co-overexpressed in gastric carcinomas and play a crucial role in gastric tumorigenesis (24). HBV has been also reported to induce COX-2 expression by recruitment of C/EBPβ to the promoter (25).…”

Section: Introductionmentioning

confidence: 99%

Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: Involvement of CCAAT/enhancer binding proteinï¿½β and cyclooxygenase-2

Ren

et al. 2011

Mol Med Report

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Abstract. Cyclooxygenase-2 (COX-2) and CCAAT/enhancer binding protein β (C/EBPβ) have been shown to be involved in inflammation and carcinogenesis, and our previous study revealed that they were co-overexpressed in human hepatocellular carcinoma (HCC) tissue and a positive correlation was found. Saikosaponin-d (SSD), a triterpene saponin extracted from Bupleurum falcatum L. (Umbelliferae), is known to exert inhibitory effects on COX-2 expression, together with inflammation and hepatic fibrosis. These findings prompted us to investigate the chemopreventive potential of SSD against hepatocarcinogenesis and its possible molecular mechanism in vivo. An experimental model with diethylinitrosamine (DEN)-treated Sprague Dawley rats was used in the present study. DEN (50 mg/kg body weight) and SSD (2 mg/kg body weight) were intraperitoneally injected weekly and daily, respectively. Administration of SSD alone had no side effects. The liver nodule formation, tumorous invasion to surrounding organs and increased cellular atypia induced by DEN were markedly reduced by SSD in the SSD + DEN group compared with the DEN group. On the other hand, immunohistochemical staining demonstrated that the expression of COX-2 and C/ EBPβ proteins was significantly increased in tumor cells and macrophages of liver tissue from DEN-treated rats, whereas the expression of the two proteins was markedly lowered in the SSD + DEN group. Overall, our results suggest that SSD prevents DEN-induced hepatocarcinogenesis in rats through inhibition of C/EBPβ and COX-2, providing indispensable experimental evidence for the clinical application of SSD as a novel chemopreventive agent against HCC in the future.

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“…It was assumed that not all GC cells exhibited increased expression of C/EBPβ; however, it was not possible to determine the percentage of GC cells that did. The expression level of C/EBPβ in GC is generally increased compared with that in healthy gastric epithelium (21). In further studies, immunohistological and flow cytometric analysis of cell cycle should be performed to improve our understanding of the expression of C/EBPα, C/EBPβ and C/EBPδ.…”

Section: Discussionmentioning

confidence: 99%

CCAAT/enhancer-binding protein α decreases the viability of gastric cancer cells

Tomizawa¹,

Shinozaki²,

Motoyoshi³

et al. 2017

Oncology Letters

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Abstract. CCAAT/enhancer-binding protein (C/EBP) α, C/EBPβ and C/EBPδ are involved in inflammation and cell differentiation. In the present study, their roles in human gastric cancer cells were investigated. The human gastric cancer cell lines MKN45 and MKN74 were subjected to the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to analyze the expression levels of C/EBPα, C/EBPβ and C/EBPδ. The cells were transfected with expression plasmids for either C/EBPα or C/EBPδ, and subjected to a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay and RT-qPCR for analysis of cyclin D1 expression. Expression levels of C/EBPα and C/EBPδ were decreased in MKN45 and MKN74 cells compared with in normal gastric tissue. Expression levels of C/EBPβ were decreased in MKN45 cells and increased in MKN74 cells. Viability of MKN45 cells was decreased by C/EBPα and C/EBPδ. Viability of MKN74 cells was decreased by C/EBPα, but increased by C/EBPδ. Expression levels of cyclin D1 were decreased in association with C/EBPα and C/EBPδ overexpression in MKN45 cells. Expression levels of cyclin D1 were decreased in association with C/EBPα overexpression, but increased in association with C/EBPδ overexpression, in MKN74 cells. The results of the present study indicate that C/EBPα is potentially useful for the treatment of gastric cancer.

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C/EBPbeta is over‐expressed in gastric carcinogenesis and is associated with COX‐2 expression

Cited by 31 publications

References 19 publications

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

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

Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: Involvement of CCAAT/enhancer binding proteinï¿½β and cyclooxygenase-2

CCAAT/enhancer-binding protein α decreases the viability of gastric cancer cells

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