RAGE is required for oval cell activation and inflammation-associated mouse liver carcinogenesis

The Receptor for Advanced Glycation-End products (RAGE) is a multiligand receptor and member of the immunoglobulin superfamily of surface receptors. RAGE is mainly involved in tissue damage and chronic inflammatory disorders, sustaining the inflammatory response by engagement with damage associated molecular pattern molecules such as S100 proteins and HMGB1. Furthermore, increased expression of RAGE and its ligands were reported in several types of tumors, enhancing tumor progression and metastasis by still unknown mechanisms. Indeed, Rage-deficient mice are protected in different mouse models of chemically induced tumorigenesis, and enhanced expression of RAGE ligands S100A8 and S100A9 in the Mdr2-/- model of inflammation-associated hepatocellular carcinoma was shown to protect cancer cells from apoptosis.Here we studied the role of RAGE in inflammation induced liver carcinogenesis in the Mdr2-/- mouse model. Rage-/- Mrd2-/- (dKO) mice developed smaller and fewer hepatocellular carcinomas than Mrd2-/- mice. Indeed, dKO mice presented mainly premalignant dysplastic nodules. Intriguingly, RAGE ablation did not affect the recruitment of inflammatory cells to the liver. However, dKO mice were protected from severe liver damage and fibrosis accompanied by decreased activation of liver oval cells, bi-lineage potential liver stem cells. Accordingly, RAGE was mainly expressed by oval cells and interference with RAGE expression in an immortalized oval cell line caused reduced cell proliferation, whereas treatment with HMGB1 promoted ERK1/2 phosphorylation and cell proliferation in vitro. In summary, our data provide experimental evidence for a crucial role of RAGE signaling in the pathogenesis of HCC, possibly via regulation of the liver stem cell pool.

Mrd2-/- inflammation HMGB1