Accelerated liver regeneration and hepatocarcinogenesis in mice overexpressing serine-45 mutant β-catenin

Nejak‐Bowen, Kari; Thompson, Michael D.; Singh, Sucha; Bowen, William C.; Dar, Mohd Jamal; Khillan, Jaspal S.; Dai, Chunsun; Monga, Satdarshan P.

doi:10.1002/hep.23538

Cited by 133 publications

(175 citation statements)

References 45 publications

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“…Hepatic GS is selectively expressed in a small population of perivenous hepatocytes (4-6, 34, 35). This expression pattern depends on Wnt-mediated activation of the transcriptional coactivator β-catenin (36,37), which is also involved in hepatocyte proliferation (38)(39)(40). Consequently, liver-specific β-catenin-deficient mice exhibit defective GS activity in the liver (36).…”

Section: Discussionmentioning

confidence: 99%

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Qvartskhava

Lang

Görg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Urea cycle defects and acute or chronic liver failure are linked to systemic hyperammonemia and often result in cerebral dysfunction and encephalopathy. Although an important role of the liver in ammonia metabolism is widely accepted, the role of ammonia metabolizing pathways in the liver for maintenance of whole-body ammonia homeostasis in vivo remains ill-defined. Here, we show by generation of liver-specific Gln synthetase (GS)-deficient mice that GS in the liver is critically involved in systemic ammonia homeostasis in vivo. Hepatic deletion of GS triggered systemic hyperammonemia, which was associated with cerebral oxidative stress as indicated by increased levels of oxidized RNA and enhanced protein Tyr nitration. Liver-specific GS-deficient mice showed increased locomotion, impaired fear memory, and a slightly reduced life span. In conclusion, the present observations highlight the importance of hepatic GS for maintenance of ammonia homeostasis and establish the liver-specific GS KO mouse as a model with which to study effects of chronic hyperammonemia.hepatic encephalopathy | metabolic zonation | oxidative stress | RNA oxidation | glutamine

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Section: Discussionmentioning

confidence: 99%

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Qvartskhava

Lang

Görg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Cells were cultured in Eagle's minimum essential medium (ATCC) supplemented with 10% fetal bovine serum and incubated in 5% CO 2 at 37 C. Purified human recombinant Wnt5a was synthesized, as described previously, and HepG2 cells were treated for 48 hours (3 mg/ mL). 13 Alternatively, the parental L cells (CRL-2648; ATCC) and Wnt5a-expressing L Wnt-5A cells (CRL-2814; ATCC) were cultured in Dulbecco's modified Eagle's medium plus 10% fetal bovine serum, with or without G-418 (Sigma, St. Louis, MO). Conditioned media were collected as per the suggested protocol.…”

Section: Cell Culture and Assaysmentioning

confidence: 99%

“…13 Briefly, an anesthetized mouse was subjected to a midline abdominal incision, and the inferior vena cava was catheterized and the portal vein was severed. After flushing, the liver was perfused gradually with collagenase (Sigma) until uniform discoloration of the liver was apparent.…”

Section: Cell Culture and Assaysmentioning

confidence: 99%

“…In addition, mouse recombinant Wnt5a (R&D) was added at 500 ng/mL to half the wells. A tritium ([ 3 H]) thymidine uptake assay was performed, as previously described, 13 on HepG2 cells treated with recombinant human Wnt5a or Wnt5a-conditioned media and ajp.amjpathol.org -The American Journal of Pathology primary mouse hepatocytes cultured in the presence of recombinant mouse Wnt5a to determine an impact on cell proliferation. Briefly, HepG2 cells were grown to approximately 50% confluence, at which time Wnt5a was added to the cultures along with 2.5 mCi/mL [ 3 H] thymidine.…”

Section: Cell Culture and Assaysmentioning

confidence: 99%

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WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Yang

Cusimano

Monga

et al. 2015

The American Journal of Pathology

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Activation of Wnt/b-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased b-catenineT-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in b-catenineT-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression.In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of b-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses b-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process. (Am J Pathol 2015, 185: 2194e2205; http:// dx

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“…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).…”

mentioning

confidence: 99%

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

Wang¹,

Yeh

Tsai³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Accelerated liver regeneration and hepatocarcinogenesis in mice overexpressing serine-45 mutant β-catenin

Cited by 133 publications

References 45 publications

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

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

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