title: 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.
authors.affiliation: IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Regalo
authors.forename: Carlos
authors.initials: C
authors.lastname: Resende
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Wen
authors.forename: Bárbara
authors.initials: B
authors.lastname: Gomes
authors.forename: Cecília
authors.initials: C
authors.lastname: Durães
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
authors.forename: José C
authors.initials: JC
authors.lastname: Machado
mesh_terms: D000328:Adult; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008297:Male; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D022762:CCAAT-Enhancer-Binding Proteins; C051838:TFF1 protein, human; D014157:Transcription Factors; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins