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.