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