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

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

ICC Jerusalem, Israel

Conferencia; EACR-AACR-ISCR Conference: The Cutting Edge of Contemporary Cancer Research; 2018

American association for cancer research (AAAC) and European association for cancer research (EACR)

Introduction. Chronic liver inflammation (CLI) is a risk factor for development ofhepatocellular carcinoma (HCC). Galectin-1 (Gal1) is involved in the regulation ofinflammation, angiogenesis and tumorigenesis, exhibiting multiple anti-inflammatory andpro-tumorigenic activities. We aimed to explore its regulatory role in CLI and HCCprogression using an established model of CLI-mediated HCC development,Mdr2(Abcb4)-knockout mice, which express high levels of Gal1 in the liver.Materials and methods. We generated double-knockout Gal1-KO/Mdr2-KO (dKO) miceon C57BL/6 and FVB/N genetic backgrounds and compared HCC development in thegenerated strains with their parental Mdr2-KO strains. Transcript expression was testedby RT-PCR and nanostring assay. Protein expression was tested by immunoblotting andimmunohistochemistry.Results and discussion. Loss of Gal1 increased liver injury, inflammation, fibrosis, andductular reaction in dKO mice starting from early age. Aged dKO mutants displayed earlierhepatocarcinogenesis and increased tumor size compared to control Mdr2-KO mice. Thiswas also accompanied by higher hepatic tumor penetrance, worsened tumordifferentiation and higher tumor cell pleomorphism in dKO mutants. Osteopontin, a well-known modulator of HCC development, was over-expressed in dKO livers at all testedanimal ages.Conclusions. Our results demonstrate that, in Mdr2-KO mice, a model of CLI-mediatedHCC, Gal1 mediated protection from hepatitis, liver fibrosis and HCC initiation, dominatesover its known pro-carcinogenic activities at later stages of HCC development.Collectively, these findings suggest that anti-Gal1 treatments may not be applicable at allstages of CLI-mediated HCC.