Expression profiling in a genetically defined mouse model of oral-esophageal dysplasia and cancer

Introduction: The development and characterization of a genetic model of oral-esophageal squamous cell cancer is important in understanding the underlying molecular mechanisms of squamous carcinogenesis. Cyclin D1 overexpression and p53 mutations are the most common genetic events in human oral/esophageal squamous cell cancer. We established a mouse model in which we demonstrate that tissue specific cyclin D1 overexpression and p53 inactivation cooperate to induce a rapid progression of dysplasia and invasive cancer specific to oral-esophageal epithelium. While abrogation of the pRb and p53 pathways is necessary for the development of oral-esophageal dysplasia and cancer, it is likely that other genetic alterations may be additionally required for the induction and progression of the malignant phenotype. Methods: To distinguish genes present in normal oral and esophageal epithelium from genes specific for oral-esophageal dysplasia, we compared the gene profiles of 6 month old cyclin D1/p53±mice and w/t mice using a NIA (National Institute of Aging) 14k murine cDNA microarray. Cyclin D1/p53±mice developed moderate to severe dysplasia at that time point. After elimination of genes with signals close to background, 5190 genes were available for statistical analysis. Results: Only 83 of the examined genes were significantly regulated in oral esophageal dysplasia when compared with the expression level of normal oral or esophageal tissue (P<0.0003). Hierarchic clustering differentiated dysplastic and normal oral or esophageal epithelium, respectively. Most of the genes identified encoded proteins involved in cellular metabolism, signaling, adhesion, apoptosis and cell cycle. Notably, within this group were p53 interacting genes like PUMA or MDM2, transcription factors like GKLF, genes associated with other GI-cancers like claudin 7 as well as a large group of unknown genes. Conclusions: Expression profiling of dysplastic and normal oral-esophageal epithelium using microarray analysis may help to identify interrelated genes involved in the pathogenesis of oral-esophageal cancer. The analysis of genes expressed in microdissected cancerous lesions compared to normal and dysplastic tissue will further define genes involved in later stages of tumor development.

Keywords: esophageal cancer, expression profiling, mouse model