INTERSTRAIN DIFFERENCES IN CHRONIC HEPATITIS AND TUMOR DEVELOPMENT IN A MURINE MODEL OF INFLAMMATION-MEDIATED CARCINOGENESIS

TAMARA POTIKHA; EVGENIY STOYANOV; ORIT PAPPO ; ANTONINA FROLOV ; LINA MIZRAHI ; DEBORAH OLAM ; TEMIMA SHNITZER-PERLMAN; IDO WEISS ; NETA BARASHI ; AMNON PELED ; GABRIELE SASS ; GISA TIEGS ; FRANCOISE POIRIER ; GABRIEL A. RABINOVICH ; EITHAN GALUN ; DANIEL GOLDENBERG

HEPATOLOGY (BALTIMORE, MD.)

JOHN WILEY & SONS INC

Lugar: New York; Año: 2013 vol. 58 p. 192 - 204

0270-9139

Chronic inflammation is strongly associated with increased risk for hepatocellular carcinoma (HCC) development. The Mdr2-knockout (Mdr2-KO, Abcb4-/-) mice, a model of inflammation-mediated HCC, develop chronic cholestatic hepatitis at early age and HCC at adult age. To delineate factors contributing to hepatocarcinogenesis, we compared the severity of early chronic hepatitis and late HCC development in two Mdr2-KO strains: FVB/N (FVB) and C57BL/6 (B6). We demonstrate that hepatocarcinogenesis was significantly less efficient in the Mdr2-KO/B6 than in the Mdr2-KO/FVB mice; this difference was more prominent in males. Chronic hepatitis in the Mdr2-KO/B6 males was more severe at one month of age, but less severe at three month of age, compared to the age-matched Mdr2-KO/FVB males. Comparative genome scale gene expression analysis of male livers of both strains at three months of age revealed both common and strain-specific aberrantly-expressed genes, including genes associated with regulation of inflammation, response to oxidative stress and lipid metabolism. One of these regulators, galectin-1 (Gal-1), possesses both anti-inflammatory and pro-tumorigenic activities. To study its regulatory role in the liver, we transferred the Gal-1-KO mutation (Lgals1-/-) from the B6 to the FVB strain, and demonstrated that endogenous Gal-1 protects the liver against Concanavalin A-induced hepatitis in the B6, but not in the FVB genetic background. Conclusion: Decreased chronic hepatitis in the Mdr2-KO/B6 mice at the age of three months correlates with a significant retardation of liver tumor development in this strain compared to the Mdr2-KO/FVB strain. We revealed candidate factors which may determine strain-specific differences in the course of chronic hepatitis and HCC development in the Mdr2-KO model, including inefficient anti-inflammatory activity of the endogenous lectin Gal-1 in the FVB strain.