High-density oligonucleotide microarrays and functional network analysis reveal extended lung carcinogenesis pathway maps and multiple interacting genes in NNK [4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone] induced CD1 mouse lung tumor

Purpose: NNK [4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone] is a nicotine-derived nitrosaminoketone contained in tobacco smoke used as a powerful chemical carcinogen for rodent experimental models of pulmonary carcinogenesis. To clarify its carcinogenetic mechanisms, we examined the expression status of 22,625 mouse genes. Methods: The affymetrix GeneChip mouse expression 430 A arrays have been used in CD1-induced mouse lung tumor. The affected genes were analyzed by Ingenuity pathway analysis to investigate functional network and gene ontology. Results: A total of 876 genes were found to be differentially expressed at least twofold between NNK-induced tumors and normal lung tissues, 390 up-regulated and 486 down-regulated in these lesions. The functions with the highest P values were related to cellular growth and proliferation (P = 1.71 × 10^-4 to 4.10 × 10^-2). In addition, we identified canonical pathways for Wnt/β-catenin signaling (P = 0.0338). Conclusions: These results suggest that application of gene expression profiling may provide an improved strategy for therapeutic targeting of tobacco smoking-induced lung cancer.