Depletion of β-catenin from mature hepatocytes of mice promotes expansion of hepatic progenitor cells and tumor development

Abstract

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...

Proteasome Dysfunction Activates Autophagy and the Keap1-Nrf2 Pathway

“…1F). The recovery of Rpt2 at P40 in the livers of Rpt2 f/f ;Alb mice might be attributed to rapid hepatocytic death due to impairment of proteasome activity, followed by compensatory regeneration of hepatocytes from oval cells, which express low levels of albumin (40). Collectively, these data indicate that at P30, Rpt2 f/f ;Alb mice exhibit liver injury accompanied by reduced proteasome activity in the liver.…”

Expansion of Hepatic Stem Cell Compartment Boosts Liver Regeneration

“…This result opens a new theoretical option for increasing the endogenous regenerative capacity of the liver. The amplification of stem/progenitor cell pool carries increased risk of tumor formation [29][30][31][32][33][34][35], although there are contradictory results as well [36]. Our results show that the DEN-AAF/CCl 4 model is as efficient a carcinogenesis model as the original Solt-Farber model and that the AAF/CCl 4 treatment is a powerful tumor promoter.…”

“…Thus, the increased number of stem cells does not indicate persistently higher tumor incidence. The recently revealed new results about the regulation of the stem cell compartment [31][32][33][34][35][36] may give us the tool to safely expand the pool of these cells in liver, which may result in clinically applicable increased regenerative capacity.…”

Function of Deubiquitinating Enzyme USP14 as Oncogene in Different Types of Cancer

“…In the cell migration assay, H1299 and MCF7 migrated cells were collected after 2h; data are the mean ± SEM of three separate experiments (D), * P < 0.05. relatively low, suggesting that USP14 might not be involved in liver cancer tumorigenesis -this may, in fact, hint toward the mechanism involved in USP14's effects on cancer. In a previous study, we found that β-catenin protein levels sharply decrease in conjunction with USP14 silencing in A549 cells [12], researchers have likewise found that β-catenin, a key member in the Wnt pathway that promotes proliferation in various tumors [33][34][35][36][37][38], is controlled through ubiquitination [39][40][41]. Given this information, SOX1, a developmental gene, may function as a tumor suppressor by interfering with Wnt/β-catenin signaling in the development of hepatocellular carcinoma.…”