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. Immunohistochemical 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.
Tsubota
Akihito
A
Institute of Clinical Medicine and Research, Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba 277-8567, Japan. atsubo@jikei.ac.jp
Matsumoto
Kenji
K
Mogushi
Kaoru
K
Nariai
Koichi
K
Namiki
Yoshihisa
Y
Hoshina
Sadayori
S
Hano
Hiroshi
H
Tanaka
Hiroshi
H
Saito
Hirohisa
H
Tada
Norio
N
D000818:Animals; D003300:Copper / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics*; D056726:Genetic Association Studies; D006527:Hepatolenticular Degeneration; D006801:Humans; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020332:Rats, Inbred LEC; D020318:Rats, Long-Evans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014746:Vimentin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020703:ras GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
C101203:IQ motif containing GTPase activating protein 1; D012333:RNA, Messenger; D014746:Vimentin; D020703:ras GTPase-Activating Proteins; D003300:Copper