Depletion of β-catenin impairs regeneration of the rapid turn-over gut epithelial cells, but appears dispensable for that of the slow turn-over mature hepatocytes in mice until 1 y of age. As the life span of mature murine hepatocytes is about 400 d, we studied conditional β-catenin knockout mice (Alb-Cre;Ctnnb1 flx/flx ) until 20 mo of age to determine the function of β-catenin in the postnatal liver. β-catenin was absent from the hepatocytes of β-catenin knockout mice 4 wk after delivery. From 9 mo of age, hepatocytes were gradually replaced by newly formed β-catenin-positive hepatocytes, which constituted about 90% of hepatocytes at 18-20 mo of age. This process was accompanied by active proliferation of bile duct/ductule cells. β-catenin-positive hepatocytes exhibited elevated proliferation activity and expression of progenitor cell markers, but lower albumin and Cre. This might explain their intact β-catenin protein, and suggest their origins from hepatic progenitor cells. Liver tumors arose spontaneously from β-catenin-positive cells, and tumorigenesis was accelerated by hepatitis B X protein.These results indicate β-catenin critical for the regeneration of mature hepatocytes. Failure to regenerate mature hepatocytes results in proliferation of hepatic progenitor cells that are able to maintain liver function but are predisposed to form liver tumors.HBx protein | liver cancer | postnatal liver regeneration T he Wnt/β-catenin pathway has long been considered involved in embryonic liver development and hepatocarcinogenesis (1, 2). However, its role in the regeneration of mature hepatocytes has remained inconclusive.In normal mature hepatocytes, the activity of this pathway is tightly controlled. Most cytosolic β-catenin is phosphorylated by glycogen synthase kinase 3β at specific serine/threonine residues, resulting in its degradation. Somatic Wnt-activation mutations of β-catenin and Axin-1 genes were identified in 20% to 30% of hepatocellular carcinoma (HCC) cases (2-4). In addition, downregulation of two negative regulators of this pathway, APC and Ecadherin (2, 5), and overexpression of the Fzd type 7 receptor were frequently observed in HCC (6), all of which result in accumulation of β-catenin. Therefore, β-catenin accumulation in the cytoplasm and nucleus is present in 50% to 70% of HCCs (7). Mutations of β-catenin also occur in the majority of childhood hepatoblastomas (8) and in a subgroup of adult hepatic adenomas predisposing to HCC (9). Activation of the Wnt/β-catenin pathway is thus considered a key event in hepatocarcinogenesis.Several transgenic (Tg) mouse models were established to investigate the role of an activated Wnt/β-catenin pathway in hepatocarcinogenesis. Tg mice expressing a Wnt-activating mutant of β-catenin in mature hepatocytes developed hepatomegaly with elevated proliferation activity but low compensatory apoptosis, but which was insufficient to cause HCC (10, 11). Additional events, such as H-ras activation or diethylnitrosamine treatment, are required for HCC formation (11, 12...

Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional β-catenin knockout mouse model. Senescent β-catenin–depleted hepatocytes in aged mice create an inflammatory microenvironment that stimulates periportal HPC expansion but arrests differentiation, which predisposes mice to the development of liver tumors. The release of complement C1q from macrophages in the inflammatory niche was identified as the unorthodox signal that activated the β-catenin pathway in periportal HPCs and was responsible for their expansion and de-differentiation. C1q inhibitors blocked the β-catenin pathway in both the expanding HPCs and the liver tumors but spared its orthodox pathway in pericentral normal hepatocytes. This mechanism has been validated in human liver specimens from patients with chronic hepatitis. Taken together, these results demonstrate that C1q- mediated activation of β-catenin pathway in periportal HPCs is a previously unrecognized mechanism for replenishing hepatocytes in the inflammatory liver and, if unchecked, for promoting hepatocarcinogenesis. C1q may become a new target for blocking carcinogenesis in patients with chronic hepatitis.