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/EBPα 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/EBPα in gastric carcinoma (GC). We analyzed the expression of C/EBPα in normal and neoplastic gastric tissues, and assessed the role of C/EBPα on proliferation and differentiation of GC cells. In normal gastric mucosa, C/EBPα is expressed in the foveolar epithelium and co-localizes with the gastric differentiation marker trefoil factor 1 (TFF1). The expression of C/EBPα was found to be lost in 30% of GC cases. To evaluate the role of C/EBPα in cell proliferation and differentiation, we transfected GC cells with a full-length C/EBPα protein. We observed a significant decrease in proliferation in C/EBPα-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/EBPα and TFF1 expression, and decreased cell proliferation and cyclin D1 expression in GC cells. Our results suggest that C/EBPα (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/EBPα may be associated with the switch from a cellular differentiation to a cellular proliferation program, presumably as a consequence of Ras/MAPK pathway activation.