IQGAP1 and vimentin are key regulator genes in naturally occurring hepatotumorigenesis induced by oxidative stress

To identify key genes involved in the complex multistep process of hepatotumorigenesis, we reduced multivariate clinicopathological variables by using the Long―Evans Cinnamon rat, a model with naturally occurring and oxidative stress-induced hepatotumorigenesis. Gene expression patterns were analyzed serially by profiling liver tissues from rats of a naive status (4 weeks old), through to those with chronic hepatitis (26 and 39 weeks old) to tumor development (67 weeks old). Of 31 099 probe sets used for microarray analysis, 87 were identified as being upregulated in a stepwise manner during disease progression and tumor development. Quantitative real-time reverse transcription―polymerase chain reaction and statistical analyses verified that IQGAP1 and vimentin mRNA expression levels increased significantly throughout hepatotumorigenesis. A hierarchical clustering algorithm showed both genes clustered together and in the same cluster group. Immunohisto-chemical and western blot analyses showed similar increases in protein levels of IAGAP1 and vimentin. Finally, pathway analyses using text-mining technology with more comprehensive and recent gene―gene interaction data identified IQGAP1 and vimentin as important nodes in underlying gene regulatory networks. These findings enhance our understanding of the multistep hepatotumorigenesis and identification of target molecules for novel treatments.