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C/EBP alpha 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/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.
AuthorsGonçalo Regalo, Carlos Resende, Xiaogang Wen, Bárbara Gomes, Cecília Durães, Raquel Seruca, Fátima Carneiro, José C Machado
JournalLaboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 90 Issue 8 Pg. 1132-9 (Aug 2010) ISSN: 1530-0307 [Electronic] United States
PMID20386538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CCAAT-Enhancer-Binding Protein-alpha
  • CCAAT-Enhancer-Binding Proteins
  • TFF1 protein, human
  • Transcription Factors
  • Trefoil Factor-1
  • Tumor Suppressor Proteins
Topics
  • Adult
  • CCAAT-Enhancer-Binding Protein-alpha (genetics, metabolism, physiology)
  • CCAAT-Enhancer-Binding Proteins (genetics, metabolism)
  • Carcinoma (genetics, pathology)
  • Cell Differentiation (genetics)
  • Cell Proliferation
  • Cell Transformation, Neoplastic (genetics)
  • Female
  • Gastric Mucosa (metabolism, pathology)
  • Homeostasis (genetics)
  • Humans
  • Male
  • Transcription Factors (genetics, metabolism)
  • Transfection
  • Trefoil Factor-1
  • Tumor Suppressor Proteins

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