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Genetic control of resistance to hepatocarcinogenesis by the mouse Hpcr3 locus

Manenti, Giacomo and Galvan, Antonella and Falvella, F. Stefania and Pascale, Rosa Maria and Spada, Elena and Milani, Silvano and González Neira, Anna and Feo, Francesco and Dragani, Tommaso A. (2008) Genetic control of resistance to hepatocarcinogenesis by the mouse Hpcr3 locus. Hepatology, Vol. 48 (2), p. 617-623. eISSN 1527-3350. Article.

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DOI: 10.1002/hep.22374

Abstract

The genome of the BALB/c mouse strain provides alleles that dominantly inhibit hepatocellular tumor development in F1 crosses with the highly hepatocarcinogenesis-susceptible C3H/He strain. Genome-wide linkage analysis using a 1536-single-nucleotide polymorphism array in a (C3H/He × BALB/c)F2 intercross population treated with urethane to induce hepatocellular tumor development revealed a locus with a major role in the resistance to hepatocarcinogenesis. This locus, designated hepatocarcinogen resistance 3 (Hpcr3) and mapping to central chromosome 15, showed a linkage at LOD score = 16.52 and accounted for 40% of the phenotypical variance. The BALB/c-derived allele at Hpcr3 reduced tumor-occupied area of the liver up to 25-fold, in a semidominant way. Additional minor loci were mapped to chromosomes 1, 10, and 18. A gene expression profile of normal adult mouse liver showed a significant association with susceptibility of BALB/c, C3H/He, and F1 mice to hepatocarcinogenesis and identified the genes expressed in the Hpcr3 locus region; moreover, this analysis implicated the E2F1 pathway in the modulation of the phenotype susceptibility to hepatocarcinogenesis. Conclusion: These findings, indicating the complex genetics of dominant resistance to hepatocarcinogenesis, represent a step toward the identification of the genes underlying this phenotype.

Item Type:Article
ID Code:1790
Status:Published
Refereed:Yes
Uncontrolled Keywords:Hepatocarcinogen resistance 3 (Hpcr3), BALB/c, hepatocellular tumorigenesis
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Wiley
eISSN:1527-3350
Copyright Holders:© 2008 by the American Association for the Study of Liver Diseases
Additional Information:Pubblicato online il 16 aprile 2008.
Deposited On:18 Aug 2009 10:06

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