title: Transcriptome profiling in oral cavity and esophagus tissues from (S)-N'-nitrosonornicotine-treated rats reveals candidate genes involved in human oral cavity and esophageal carcinogenesis.
abstract: Recently, we have shown that (S)-N'-Nitrosonornicotine [(S)-NNN], the major form of NNN in tobacco products, is a potent oral cavity and esophageal carcinogen in rats. To determine the early molecular alterations induced by (S)-NNN in the oral and esophageal mucosa, we administered the carcinogen to rats in the drinking water for 10 wk and global gene expression alterations were analyzed by RNA sequencing. At a false discovery rate P-value < 0.05 and fold-change ≥2, we found alterations in the level of 39 genes in the oral cavity and 69 genes in the esophagus. Validation of RNA sequencing results by qRT-PCR assays revealed a high cross-platform concordance. The most significant impact of exposure to (S)-NNN was alteration of genes involved in immune regulation (Aire, Ctla4, and CD80), inflammation (Ephx2 and Inpp5d) and cancer (Cdkn2a, Dhh, Fetub B, Inpp5d, Ly6E, Nr1d1, and Wnt6). Consistent with the findings in rat tissues, most of the genes were deregulated, albeit to different degrees, in immortalized oral keratinocytes treated with (S)-NNN and in non-treated premalignant oral cells and malignant oral and head and neck squamous cells. Furthermore, interrogation of TCGA data sets showed that genes deregulated by (S)-NNN in rat tissues (Fetub, Ly6e, Nr1d1, Cacna1c, Cd80, and Dgkg) are also altered in esophageal and head and neck tumors. Overall, our findings provide novel insights into early molecular changes induced by (S)-NNN and, therefore, could contribute to the development of biomarkers for the early detection and prevention of (S)-NNN-associated oral and esophageal cancers. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota.
authors.forename: Ali
authors.initials: A
authors.lastname: Khammanivong
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Arunkumar
authors.initials: A
authors.lastname: Anandharaj
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Qian
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Song
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Pramod
authors.initials: P
authors.lastname: Upadhyaya
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Environmental Health Sciences Division, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Silvia
authors.initials: S
authors.lastname: Balbo
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Dipankar
authors.initials: D
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Dickerson
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Hecht
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Fekadu
authors.initials: F
authors.lastname: Kassie
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics*; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000235:genetics*; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009055:Mouth / Q000187:drug effects / Q000378:metabolism; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000235:genetics*; D009602:Nitrosamines / Q000008:administration & dosage / Q000633:toxicity*; D011916:Rats, Inbred F344; D059467:Transcriptome
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; C008655:N'-nitrosonornicotine
keywords: N′-nitrosonornicotine; RNA sequencing; gene expression; soluble epoxide hydrolase