Deficiency of CCAAT/enhancer binding protein family DNA binding prevents malignant conversion of adenoma to carcinoma in NNK-induced lung carcinogenesis in the mouse

Shioko Kimura,Taketomo Kido,Jorge Paiz,Charles Vinson,Mitsuhiro Yoneda,Jerrold M Ward

doi:10.1186/1476-4598-11-90

Abstract

BackgroundThe CCAAT/enhancer binding proteins (C/EBPs) play important roles in carcinogenesis of many tumors including the lung. Since multiple C/EBPs are expressed in lung, the combinatorial expression of these C/EBPs on lung carcinogenesis is not known.MethodsA transgenic mouse line expressing a dominant negative A-C/EBP under the promoter of lung epithelial Clara cell secretory protein (CCSP) gene in doxycycline dependent fashion was subjected to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis bioassay in the presence and absence of doxycycline, and the effect of abolition of DNA binding activities of C/EBPs on lung carcinogenesis was examined.ResultsA-C/EBP expression was found not to interfere with tumor development; however, it suppressed the malignant conversion of adenoma to carcinoma during NNK-induced lung carcinogenesis. The results suggested that Ki67 may be used as a marker for lung carcinomas in mouse.ConclusionsThe DNA binding of C/EBP family members can be used as a potential molecular target for lung cancer therapy.

Highlights

The CCAAT/enhancer binding proteins (C/EBPs) play important roles in carcinogenesis of many tumors including the lung
One section showed higher positive staining in benign areas than carcinomas (1 out of 73 lung sections analyzed). These results suggested that A-C/EBP expression in the presence of Dox may interfere with malignant conversion of adenoma to carcinoma in A-C/EBP+ mice
A-C/EBP expression appeared to have inhibited the malignant conversion of adenoma to carcinoma in mice expressing A-C/EBP when the expression was initiated at 52 weeks post-1st NNK administration, the time when tumors had already been well developed, and the mice necropsied at 62 weeks post-1st NNK administration

Summary

Introduction

The CCAAT/enhancer binding proteins (C/EBPs) play important roles in carcinogenesis of many tumors including the lung. The CCAAT/enhancer binding proteins (C/EBPs) are a family of basic leucine zipper (B-ZIP) transcription factors that play important roles in cellular differentiation, proliferation, survival, and apoptosis, and metabolism, inflammation, and transformation [1,2,3]. Six C/EBP family members have been identified that share the N-terminal basic amino acid-containing region necessary for DNA binding and the highly conservative C-terminal leucine zipper (B-ZIP) dimerization motif [4,5]. One of the C/EBPβ isoforms, the C/EBP-liverenriched inhibitory protein acts as dominant-negative, and the increased expression inhibits the transcriptional activation of genes involved in differentiation, while its over-expression is found in breast cancers [13,14]

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