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 anticancer treatment efficacy and reduced survival time. A detailed understanding of the cellular mechanisms that are affected by tobacco smoke should facilitate the development of improved preventive and therapeutic strategies. We have investigated the effects of a tobacco smoke (TS) extract on the transcriptome of MSK-Leuk1 cells, a cellular model of oral leukoplakia. Using Affymetrix HGU133 Plus 2 arrays, 411 differentially expressed probesets 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 appeared to be perturbed. Analysis of networks connecting the affected genes identified specific molecular interactions, hubs and key transcription regulators affected by TS. Thus TS was found to induce several EGFR ligands forming an EGFR-centered molecular interaction network, as well as several AhR-dependent genes, including the xenobiotic metabolizing enzymes CYP1A1 and CYP1B1. Notably, the latter findings in vitro are consistent with our parallel finding that levels of CYP1A1 and CYP1B1 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 AhR signaling will prevent or delay the development of tobacco smoke-related tumors. Moreover, the inductive effects of TS on xenobiotic metabolizing enzymes may help explain reduced efficacy of chemotherapy, and suggest targets for chemopreventive agents in smokers.

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Gümüş ZH, Du B, Kacker A, Boyle JO, Bocker JM, Mukherjee P, Subbaramaiah K, Dannenberg AJ, Weinstein H