Effects of tobacco smoke on gene expression and cellular pathways in a cellular model of oral leukoplakia.
In addition to being causally linked to the formation of multiple tumor types, tobacco use has been associated with decreased efficacy of anticancer treatment and reduced survival time. A detailed understanding of the cellular mechanisms that are affected by tobacco smoke (TS) should facilitate the development of improved preventive and therapeutic strategies. We have investigated the effects of a TS extract on the transcriptome of MSK-Leuk1 cells, a cellular model of oral leukoplakia. Using Affymetrix HGU133 Plus 2 arrays, 411 differentially expressed probe sets were identified. The observed transcriptome changes were grouped according to functional information and translated into molecular interaction network maps and signaling pathways. Pathways related to cellular proliferation, inflammation, apoptosis, and tissue injury seemed to be perturbed. Analysis of networks connecting the affected genes identified specific modulated molecular interactions, hubs, and key transcription regulators. Thus, TS was found to induce several epidermal growth factor receptor (EGFR) ligands forming an EGFR-centered molecular interaction network, as well as several aryl hydrocarbon receptor-dependent genes, including the xenobiotic metabolizing enzymes CYP1A1 and CYP1B1. Notably, the latter findings in vitro are consistent with our parallel finding that CYP1A1 and CYP1B1 levels were increased in oral mucosa of smokers. Collectively, these results offer insights into the mechanisms underlying the procarcinogenic effects of TS and raise the possibility that inhibitors of EGFR or aryl hydrocarbon receptor signaling will prevent or delay the development of TS-related tumors. Moreover, the inductive effects of TS on xenobiotic metabolizing enzymes may help explain the reduced efficacy of chemotherapy, and suggest targets for chemopreventive agents in smokers.
Gümüş
Zeynep H
ZH
Department of Physiology and Biophysics, Weill Medical College of Cornell University, Box 75, Room E-509, 1300 York Avenue, New York, NY 10065, USA.
Du
Baoheng
B
Kacker
Ashutosh
A
Boyle
Jay O
JO
Bocker
Jennifer M
JM
Mukherjee
Piali
P
Subbaramaiah
Kotha
K
Dannenberg
Andrew J
AJ
Weinstein
Harel
H
D001189:Aryl Hydrocarbon Hydroxylases; D002478:Cells, Cultured; D016000:Cluster Analysis; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007972:Leukoplakia, Oral / Q000235:genetics* / Q000473:pathology*; D008954:Models, Biological; D009061:Mouth Mucosa / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics; D012907:Smoking / Q000009:adverse effects / Q000235:genetics* / Q000378:metabolism
D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1