Down-Regulation and Antiproliferative Role of C/EBP{alpha} in Lung Cancer

Molecular Biology and Genetics

Down-Regulation and Antiproliferative Role of C/EBP ${alpha}$ in Lung Cancer¹

Balazs Halmos, Claudia S. Huettner, Olivier Kocher, Katalin Ferenczi, Daniel D. Karp and Daniel G. Tenen²

Division of Hematology/Oncology, Departments of Medicine [B. H., D. D. K.] and Pathology [O. K.], Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, and Harvard Institutes of Medicine, Harvard Medical School [C. S. H., D. G. T.] and Department of Dermatology, Brigham and Women‘s Hospital, HIM-660 [K. F.], Boston, Massachusetts 02115

The transcription factor, CCAAT/enhancer binding protein ${alpha}$ (C/EBP ${alpha}$ )is important in the terminal differentiation of granulocytes,hepatocytes, and adipocytes, and recurrent mutations of C/EBP ${alpha}$ were described in acute myeloid leukemia. In the lung, C/EBP ${alpha}$ is expressed in bronchial cells and type II pneumocytes. Abnormalproliferation of the latter cell type was reported in C/EBP ${alpha}$ knockout mice. We determined the expression of C/EBP ${alpha}$ by Northernblot analysis in 30 lung cancer cell lines and found significantdown-regulation in 24 cell lines. Immunohistochemical studyof primary tumor specimens showed undetectable or low expressionof C/EBP ${alpha}$ in 23 of 53 specimens. Its expression was more frequentlydown-regulated in adenocarcinoma and poorly differentiated cancerspecimens than in squamous cell cancers. A higher frequencyof reduced expression was found in more advanced stages. Toinvestigate the consequences of C/EBP ${alpha}$ expression in lung cancercells, we stably transfected two cell lines that do not expressthe gene (Calu1 and H358) with a plasmid allowing for inductionof C/EBP ${alpha}$ protein expression. Induction of C/EBP ${alpha}$ led to significantgrowth reduction attributable to proliferation arrest, morphologicalchanges characteristic of differentiation, and apoptosis. Theseresults suggest that C/EBP ${alpha}$ is down-regulated in a large proportionof lung cancers and that it has growth-inhibitory propertiesin airway epithelial cells. Genetic analysis of the C/EBP ${alpha}$ geneis in progress to fully evaluate its role as a novel tumor suppressorin lung cancer.

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