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Effects of Tobacco Smoke on Gene Expression and Cellular Pathways in a Cellular Model of Oral Leukoplakia

Zeynep H. Gümü^1,4, Baoheng Du², Ashutosh Kacker³, Jay O. Boyle⁵, Jennifer M. Bocker^2,5, Piali Mukherjee⁴, Kotha Subbaramaiah², Andrew J. Dannenberg² and Harel Weinstein^1,4

Authors' Affiliations: ¹ Physiology and Biophysics, ² Medicine, and ³ Otolaryngology, and ⁴ HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University; and ⁵ Department of Surgery (Head and Neck Service), Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Harel Weinstein, Department of Physiology and Biophysics, Weill Medical College of Cornell University, Box 75, Room E-509, 1300 York Avenue, New York, NY 10065. Phone: 212-746-6358; Fax: 212-746-8690; E-mail: haw2002{at}med.cornell.edu.

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.

Key Words: microarray • tobacco smoke • gene expression • oral • aryl hydrocarbon receptor

Commentary

Genomics of Smoking Exposure and Cessation: Lessons for Cancer Prevention and Treatment

Trevor M. Penning and Caryn Lerman
Cancer Prevention Research 2008 1: 80-83. [Full Text] [PDF]