Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

POTIKHA, TAMARA; PAPPO, ORIT; MIZRAHI, LINA; OLAM, DEVORAH; MALLER, SEBASTIÁN M.; RABINOVICH, GABRIEL A.; GALUN, EITHAN; GOLDENBERG, DANIEL S.

FASEB JOURNAL

FEDERATION AMER SOC EXP BIOL

Año: 2019

0892-6638

ABSTRACTChronic liver inflammation (CLI) is a risk factor for development of hepatocellular carcinoma (HCC). Galectin-1 (Gal1) is involved in the regulation of inflammation, angiogenesis and tumorigenesis, exhibiting multiple anti-inflammatory and pro-tumorigenic activities. We aimed to explore its regulatory role in CLI and HCC progression using an established model of CLI-mediated HCC development, Mdr2(Abcb4)-knockout mice, which express high levels of Gal1 in the liver. We generated double-knockout Gal1-KO/Mdr2-KO (dKO) mice on C57BL/6 and FVB/N genetic backgrounds and compared HCC development in the generated strains with their parental Mdr2-KO strains. Loss of Gal1 increased liver injury, inflammation, fibrosis, and ductular reaction in dKO mice of both strains starting from early age. Aged dKO mutants displayed earlier hepatocarcinogenesis and increased tumor size compared to control Mdr2-KO mice. We found that osteopontin, a well-known modulator of HCC development, and oncogenic proteins Ntrk2 (TrkB) and S100A4 were over-expressed in dKO compared to Mdr2-KO livers. Our results demonstrate that, in Mdr2-KO mice, a model of CLI-mediated HCC, Gal1-mediated protection from hepatitis, liver fibrosis and HCC initiation, dominates over its known pro-carcinogenic activities at later stages of HCC development. These findings suggest that anti-Gal1 treatments may not be applicable at all stages of CLI-mediated HCC.