Molecular characterization of lung dysplasia induced by c-Raf-1.
BACKGROUND
Lung cancer is a multistage process with poor prognosis and high morbidity. Importantly, the genetics of dysplasia, a facultative cancer, at the edge of malignant transformation is unknown.


RESULTS
We employed laser microdissection to harvest c-Raf1- induced dysplastic as opposed to transgenic but otherwise morphologically unaltered epithelium and compared findings to non-transgenic lung. We then employed microarrays to search genome wide for gene regulatory networks. A total of 120 and 287 genes were significantly regulated, respectively. Dysplasia was exclusive associated with up-regulation of genes coding for cell growth and proliferation, cell-to-cell signalling and interaction, lipid metabolism, development, and cancer. Likewise, when dysplasia was compared with non-transgenic cells up-regulation of cancer associated genes, tight junction proteins, xenobiotic defence and developmental regulators was observed. Further, in a comparison of the data sets of dysplasia vs transgenic and dysplasia vs non-transgenic 114 genes were regulated in common. We additionally confirmed regulation of some genes by immunohistochemistry and therefore demonstrate good concordance between gene regulation and coded protein.


CONCLUSIONS
Our study identified transcriptional networks at successive stages of tumor-development, i.e. from histological unaltered but transgenic lungs to nuclear atypia. Our SP-C/c-raf transgenic mouse model revealed interesting and novel candidate genes and pathways that provide clues on the mechanism forcing respiratory epithelium into dysplasia and subsequently cancer, some of which might also be useful in the molecular imaging and flagging of early stages of disease.
Rohrbeck
Astrid
A
Department of Molecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
Müller
Volker Steffen
VS
Borlak
Jürgen
J
D000818:Animals; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D007150:Immunohistochemistry; D008171:Lung Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019908:Proto-Oncogene Proteins c-raf