Cancer genomics identifies regulatory gene networks associated with the transition from dysplasia to adenocarcinomas

ABSTRACT: Lung cancer is a leading cause of deaths in the world. There is a need to improve an understanding of mechanisms of malignant transformation and to develop genetic markers of disease for better and targeted therapies. Here, we report findings with a transgenic disease model where targeted expression of c-raf to respiratory epithelium induced adenocarcinomas. Specifically, by use of laser microdissection we harvested either tumor or transgenic and non-transgenic but otherwise morphologically unaltered cells. We then searched genome wide for regulated genes and validated results by quantitative real-time PCR. Overall, 473 and 541 genes were significantly regulated when cancer versus transgenic and cancer versus non-transgenic cells were compared. Principal component analysis and hierarchical clustering of the data clearly separated the cancer cells from transgenic and non-transgenics and we observed predominately repression of gene expression at advanced stages of tumor growth. Nonetheless genes up-regulated in dysplasia were also up-regulated in solid tumors. We observed groups of genes acting in concert either linked to development with an unexpected high number of genes coding either for the epithelial mesenchymal or mesenchymal endothelial transition. Additionally, genes coding for cell adhesion including the integrins and the tight and gap junction proteins were repressed (integrin alpha 1, integrin alpha 8, claudin 2, claudin 5, gap junction membrane channel protein alpha 5 and cadherin 5) but ligands for the membrane bound epidermal growth factor tyrosine kinase i.e. epi- and amphiregulin were up-regulated. Moreover, molecules in the signalling of vascular endothelial growth factor receptor- 2 and VEGFD, Notch and WNT were regulated as were glycosylases that facilitate cellular recognition. Other regulated signalling molecules included exchange factor such as RAP guanine nucleotide exchange factor 3, RHO guanine nucleotide exchange factor 10, RAS guanine releasing protein 2 and 3, and RAS guanine nucleotide-releasing factor 1 that play a role in an activation of the MAP kinases. Notably, we found the tumor suppressors MCC (mutated in colorectal cancers), HEY1 (hairy/enhancer-of-split related with YRPW motif 1), FAT3 (FAT tumor suppressor homolog 3), ARMCX1 (armadillo repeat containing, X-linked 1) and RECK (reversion-inducing-cysteine-rich protein with kazal motifs) to be significantly repressed. Taken collectively, our study provides valuable information for new candidate genes in lung adenocarcinoma induced by exaggerted c-raf kinase activity.

ORGANISM(S): Mus musculus

PROVIDER: GSE14277 | GEO | 2011/03/07

SECONDARY ACCESSION(S): PRJNA111245

REPOSITORIES: GEO