C/EBPα expression is associated with homeostasis of the gastric epithelium and with gastric carcinogenesis

Abstract

Transcription factors from the CCAAT/enhancer-binding protein (C/EBP) family are fundamental for the control of differentiation and proliferation of many adult tissues. C/EBPa has a crucial role in inducing terminal differentiation and is an established tumor suppressor gene in several cancer models. The objective of this study was to analyze the putative role of C/EBPa in gastric carcinoma (GC). We analyzed the expression of C/EBPa in normal and neoplastic gastric tissues, and assessed the role of C/EBPa on proliferation and differentiation of GC cells. In normal gastric mucosa, C/EBPa is expressed in the foveolar epithelium and co-localizes with the gastric differentiation marker trefoil factor 1 (TFF1). The expression of C/EBPa was found to be lost in 30% of GC cases. To evaluate the role of C/EBPa in cell proliferation and differentiation, we transfected GC cells with a full-length C/EBPa protein. We observed a significant decrease in proliferation in C/EBPa-transfected cells. This was accompanied by a decrease in Cyclin D1, an increase in P27 expression, and an increased expression of TFF1. Finally, we showed that inhibition of the Ras/MAPK pathway leads to increased C/EBPa and TFF1 expression, and decreased cell proliferation and cyclin D1 expression in GC cells. Our results suggest that C/EBPa (together with other members of the C/EBP family) has an active role in the control of differentiation and proliferation in normal gastric mucosa. In GC, loss of C/EBPa may be associated with the switch from a cellular differentiation to a cellular proliferation program, presumably as a consequence of Ras/MAPK pathway activation.

Down-regulation of the expression of CCAAT/enhancer binding protein α gene in cervical squamous cell carcinoma

“…C/EBPα is aberrantly silenced in pancreatic cancer cells and restored C/EBPα gene expression markedly suppressed proliferation of pancreatic cancer cells [13]. In gastric carcinoma, loss of C/EBPα is associated with the switch from cellular differentiation to cellular proliferation, presumably as a result of the activation of Ras/MAPK pathway [14]. In addition, methylation in the promoter of C/EBPα gene occurred at a rate of 24% in dedifferentiated liposarcoma (DLPS).…”

Trefoil factors: Gastrointestinal-specific proteins associated with gastric cancer

“…Through C/EBPα(CCAAT/enhancer-binding protein α) signaling pathway, the expression of TFF1 is increased and GC cells have a pronounced reducing in proliferation [129]. Soutto et al [130] reported that loss of TFF1 facilitated β-catenin activation and gastric tumorigenesis through AKT/GSK3β/β-catenin signaling pathway.…”

C/EBPα Suppresses Lung Adenocarcinoma Cell Invasion and Migration by Inhibiting β-Catenin

“…As a tumor suppressor, C/EBPα was found to be downregulated in several types of cancer and regulated cancer cell behaviors such as proliferation, differentiation and metabolism [12, 13]. In the lung, C/EBPα is highly expressed in alveolar type II cells, Clara cells, and alveolar macro-phages [14, 15].…”