{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T22:23:30Z","timestamp":1778711010855,"version":"3.51.4"},"reference-count":51,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T00:00:00Z","timestamp":1453161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA\u201081301"],"award-info":[{"award-number":["CA\u201081301"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec><jats:label\/><jats:p>Recently, we have shown that (<jats:italic>S<\/jats:italic>)\u2010<jats:italic>N<\/jats:italic>'\u2010Nitrosonornicotine [(<jats:italic>S<\/jats:italic>)\u2010NNN], 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 (<jats:italic>S<\/jats:italic>)\u2010NNN in the oral and esophageal mucosa, we administered the carcinogen to rats in the drinking water for 10\u2009wk and global gene expression alterations were analyzed by RNA sequencing. At a false discovery rate <jats:italic>P<\/jats:italic>\u2010value\u2009&lt;\u20090.05 and fold\u2010change \u22652, 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\u2010PCR assays revealed a high cross\u2010platform concordance. The most significant impact of exposure to (<jats:italic>S<\/jats:italic>)\u2010NNN was alteration of genes involved in immune regulation (<jats:italic>Aire<\/jats:italic>, <jats:italic>Ctla4<\/jats:italic>, and <jats:italic>CD80<\/jats:italic>), inflammation (<jats:italic>Ephx2<\/jats:italic> and <jats:italic>Inpp5d<\/jats:italic>) and cancer (<jats:italic>Cdkn2a<\/jats:italic>, <jats:italic>Dhh<\/jats:italic>, <jats:italic>Fetub B<\/jats:italic>, <jats:italic>Inpp5d<\/jats:italic>, <jats:italic>Ly6E<\/jats:italic>, <jats:italic>Nr1d1<\/jats:italic>, and <jats:italic>Wnt6<\/jats:italic>). Consistent with the findings in rat tissues, most of the genes were deregulated, albeit to different degrees, in immortalized oral keratinocytes treated with (<jats:italic>S<\/jats:italic>)\u2010NNN and in non\u2010treated premalignant oral cells and malignant oral and head and neck squamous cells. Furthermore, interrogation of TCGA data sets showed that genes deregulated by (<jats:italic>S<\/jats:italic>)\u2010NNN in rat tissues (<jats:italic>Fetub<\/jats:italic>, <jats:italic>Ly6e<\/jats:italic>, <jats:italic>Nr1d1<\/jats:italic>, <jats:italic>Cacna1c<\/jats:italic>, <jats:italic>Cd80<\/jats:italic>, and <jats:italic>Dgkg<\/jats:italic>) are also altered in esophageal and head and neck tumors. Overall, our findings provide novel insights into early molecular changes induced by (<jats:italic>S<\/jats:italic>)\u2010NNN and, therefore, could contribute to the development of biomarkers for the early detection and prevention of (<jats:italic>S<\/jats:italic>)\u2010NNN\u2010associated oral and esophageal cancers. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mc.22459","type":"journal-article","created":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T16:07:12Z","timestamp":1453219632000},"page":"2168-2182","source":"Crossref","is-referenced-by-count":9,"title":["Transcriptome profiling in oral cavity and esophagus tissues from (<i>S<\/i>)\u2010N\u2032\u2010nitrosonornicotine\u2010treated rats reveals candidate genes involved in human oral cavity and esophageal carcinogenesis"],"prefix":"10.1002","volume":"55","author":[{"given":"Ali","family":"Khammanivong","sequence":"first","affiliation":[{"name":"Department of Veterinary Clinical Sciences College 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Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Balbo","sequence":"additional","affiliation":[{"name":"Masonic Cancer Center University of Minnesota Minneapolis Minnesota"},{"name":"Environmental Health Sciences Division School of Public Health, University of Minnesota Minneapolis Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dipankar","family":"Bandyopadhyay","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Virginia Commonwealth University Richmond Virginia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin B.","family":"Dickerson","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences College of Veterinary Medicine, University of Minnesota Saint Paul Minnesota"},{"name":"Masonic Cancer Center University of Minnesota Minneapolis Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen 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