Human Molecular Genetics Advance Access originally published online on May 19, 2009
Human Molecular Genetics 2009 18(16):2975-2988; doi:10.1093/hmg/ddp236
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Diet-induced hepatocellular carcinoma in genetically predisposed mice
1 Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA 2 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA 3 Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA 4 Department of Bioengineering, University of California, San Diego, CA 93093, USA 5 Case Center for Transdisciplinary Research on Energetics and Cancer 6 Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
* To whom correspondence should be addressed at: Department of Genetics, BRB731, CWRU, 10900 Euclid Ave, Cleveland, OH 44106, USA. Email: joseph.nadeau{at}case.edu or jhn4{at}case.edu
Received January 5, 2009; Accepted May 14, 2009
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, with 
70% of cases resulting from hepatitis B and C viral infections, aflatoxin exposure, chronic alcohol use or genetic liver diseases. The remaining 30% of cases are associated with obesity, type 2 diabetes and related metabolic diseases, although a direct link between these pathologies and HCCs has not been established. We tested the long-term effects of high-fat and low-fat diets on males of two inbred strains of mice and discovered that C57BL/6J but not A/J males were susceptible to non-alcoholic steatohepatitis (NASH) and HCC on a high-fat but not low-fat diet. This strain–diet interaction represents an important model for genetically controlled, diet-induced HCC. Susceptible mice showed morphological characteristics of NASH (steatosis, hepatitis, fibrosis and cirrhosis), dysplasia and HCC. mRNA profiles of HCCs versus tumor-free liver showed involvement of two signaling networks, one centered on Myc and the other on NF
B, similar to signaling described for the two major classes of HCC in humans. miRNA profiles revealed dramatically increased expression of a cluster of miRNAs on the X chromosome without amplification of the chromosomal segment. A switch from high-fat to low-fat diet reversed these outcomes, with switched C57BL/6J males being lean rather than obese and without evidence for NASH or HCCs at the end of the study. A similar diet modification may have important implications for prevention of HCCs in humans.
These authors contributed equally to the work reported in this paper.