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.
OBJECTIVE
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 x 10(-4) to 4.10 x 10(-2)). In addition, we identified canonical pathways for Wnt/beta-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.
Abdel-Aziz
Hekmat Osman
HO
Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Takasaki
Ichiro
I
Tabuchi
Yoshiaki
Y
Nomoto
Kazuhiro
K
Murai
Yoshihiro
Y
Tsuneyama
Koichi
K
Takano
Yasuo
Y
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000187:drug effects*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D008954:Models, Biological; D009602:Nitrosamines / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction
D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone