title: Overexpression of lipocalins and pro-inflammatory chemokines and altered methylation of PTGS2 and APC2 in oral squamous cell carcinomas induced in rats by 4-nitroquinoline-1-oxide.
abstract: Oral squamous cell carcinomas (OSCC) induced in F344 rats by 4-nitroquinoline-1-oxide (4-NQO) demonstrate considerable phenotypic similarity to human oral cancers. Gene expression studies (microarray and PCR) were coupled with methylation analysis of selected genes to identify molecular markers of carcinogenesis in this model and potential biochemical and molecular targets for oral cancer chemoprevention. Microarray analysis of 11 pairs of OSCC and site-matched phenotypically normal oral tissues from 4-NQO-treated rats identified more than 3500 differentially expressed genes; 1735 genes were up-regulated in rat OSCC versus non-malignant tissues, while 1803 genes were down-regulated. In addition to several genes involved in normal digestion, genes demonstrating the largest fold increases in expression in 4-NQO-induced OSCC include three lipocalins (VEGP1, VEGP2, LCN2) and three chemokines (CCL, CXCL2, CXCL3); both classes are potentially druggable targets for oral cancer chemoprevention and/or therapy. Down-regulated genes in 4-NQO-induced OSCC include numerous keratins and keratin-associated proteins, suggesting that alterations in keratin expression profiles may provide a useful biomarker of oral cancer in F344 rats treated with 4-NQO. Confirming and extending our previous results, PTGS2 (cyclooxygenase-2) and several cyclooxygenase-related genes were significantly up-regulated in 4-NQO-induced oral cancers; up-regulation of PTGS2 was associated with promoter hypomethylation. Rat OSCC also demonstrated increased methylation of the first exon of APC2; the increased methylation was correlated with down-regulation of this tumor suppressor gene. Overexpression of pro-inflammatory chemokines, hypomethylation of PTGS2, and hypermethylation of APC2 may be causally linked to the etiology of oral cancer in this model.
authors: Life Sciences Group, IIT Research Institute, Chicago, Illinois, 60616, United States of America.
authors: Xinjian
authors: X
authors: Peng
authors: Life Sciences Group, IIT Research Institute, Chicago, Illinois, 60616, United States of America.
authors: Wenping
authors: W
authors: Li
authors: Life Sciences Group, IIT Research Institute, Chicago, Illinois, 60616, United States of America.
authors: William D
authors: WD
authors: Johnson
authors: GenUs Biosystems, Northbrook, Illinois, 60062, United States of America.
authors: Karen E O
authors: KE
authors: Torres
authors: Life Sciences Group, IIT Research Institute, Chicago, Illinois, 60616, United States of America.
authors: David L
authors: DL
authors: McCormick
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D007633:Keratins / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011916:Rats, Inbred F344; D014059:Tongue / Q000473:pathology; D059467:Transcriptome
chemical_list: D018925:Chemokines; D054834:Lipocalins; D008565:Membrane Proteins; D015112:4-Nitroquinoline-1-oxide; D007633:Keratins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat
references: Biol Chem. 2012 Apr;393(5):391-401
references: 22505521
references: Prostate. 2013 Sep;73(12):1281-90
references: 23775308
references: Bioinformatics. 2002 Nov;18(11):1427-31
references: 12424112
references: Dis Markers. 2008;25(1):1-16
references: 18776587
references: Tumour Biol. 2014 May;35(5):4673-85
references: 24430362
references: Oncol Rep. 2011 Dec;26(6):1415-21
references: 21874256
references: PLoS One. 2013;8(7):e70688
references: 23936238
references: Hum Pathol. 2011 Mar;42(3):409-18
references: 21193224
references: J Biol Chem. 2013 May 10;288(19):13641-54
references: 23511635
references: Jpn J Cancer Res. 1992 Aug;83(8):843-50
references: 1399822
references: Expert Opin Ther Targets. 2011 Sep;15(9):1037-47
references: 21609295
references: Oral Oncol. 2014 May;50(5):380-6
references: 24461628
references: Cancer. 2011 Jun 15;117(12):2608-19
references: 21656738
references: PLoS One. 2013;8(8):e70442
references: 23936432
references: J Chronic Dis. 1972 Dec;25(12):711-6
references: 4648515
references: Oral Oncol. 2013 Dec;49(12):1129-35
references: 24120275
references: Clin Cancer Res. 2000 Dec;6(12):4684-91
references: 11156220
references: Cancer Sci. 2003 Apr;94(4):365-71
references: 12824906
references: Prog Mol Biol Transl Sci. 2010;95:31-53
references: 21075328
references: Biochim Biophys Acta. 2012 Aug;1826(1):129-69
references: 22513004
references: Br J Cancer. 2007 Jan 29;96(2):362-72
references: 17242704
references: J Exp Med. 2013 Nov 18;210(12):2661-73
references: 24166712
references: Oncogenesis. 2012 Jul 09;1:e23
references: 23552739
references: Mayo Clin Proc. 2007 Jul;82(7):878-87
references: 17605971
references: J Carcinog. 2012;11:14
references: 23233820
references: Am J Epidemiol. 2013 Sep 1;178(5):679-90
references: 23817919
references: Nutr Cancer. 1993;19(2):191-200
references: 8502589
references: J Gen Virol. 2011 Feb;92(Pt 2):395-401
references: 21048034
references: Mod Pathol. 2012 Jun;25(6):784-94
references: 22301701
references: Tumour Biol. 2014 Oct;35(10):10539-46
references: 25060177
references: Oncol Rep. 2007 Nov;18(5):1107-13
references: 17914560
references: Recent Results Cancer Res. 2014;193:135-48
references: 24008297
references: Anticancer Res. 2014 Feb;34(2):1021-5
references: 24511049
references: J Immunol. 2012 Nov 1;189(9):4528-36
references: 23008450
references: Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3913-8
references: 19237579
references: Cancer Chemother Pharmacol. 2013 Apr;71(4):1041-50
references: 23385782
references: J Cell Physiol. 2011 Feb;226(2):309-14
references: 20857428
references: Contemp Oncol (Pozn). 2013;17(1):64-7
references: 23788964
references: Laryngoscope. 2003 Oct;113(10):1687-702
references: 14520092
references: Carcinogenesis. 2014 Jun;35(6):1362-70
references: 24531940
references: Planta Med. 2013 Mar;79(3-4):227-35
references: 23345168
references: Cancer Res. 1988 Jun 1;48(11):3282-7
references: 3365707
references: Clin Cancer Res. 2014 Feb 1;20(3):688-700
references: 24240113
references: Cancer Prev Res (Phila). 2010 Jan;3(1):73-81
references: 20051374
references: Patholog Res Int. 2011;2011:431246
references: 21660266
references: CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29
references: 24399786
references: Biochem Biophys Res Commun. 2012 Aug 3;424(3):456-61
references: 22771802
references: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references: 21296855
references: Am J Clin Nutr. 1998 Dec;68(6 Suppl):1406S-1412S
references: 9848508
references: J Dig Dis. 2012 Apr;13(4):208-13
references: 22435505
references: Cancer Prev Res (Phila). 2009 Feb;2(2):128-33
references: 19174582
references: Cancer Prev Res (Phila). 2013 May;6(5):410-8
references: 23639862