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P53 deletion induces liver carcinoma with bilineal differentiation

ABSTRACT: Background and Aims: p53 can limit the self-renewal of stem cells from various tissues. Experimental evidence suggests that deletion of p53 can cooperate with other oncogenic events to induce aberrant self-renewal and transformation of progenitor cells. It is not known whether p53 deletion alone can lead to liver tumor formation. Methods: We used AlfpCre mice for liver-specific deletion of Trp53 in a conditional knockout mouse model to analyze liver carcinogenesis. Results: Here, we show that liver-specific deletion of p53 in mice consistently induces formation of liver carcinoma depicting bilineal differentiation. Freshly isolated p53-/- liver progenitor cells and hepatocytes exhibit chromosomal imbalances and an enhanced clonogenic capacity compared to p53-positive cells or p21-deficient cells. Primary cultures of hepatocytes and liver progenitor cells from p53-/- mice formed tumors with bilineal differentiation when transplanted into immuno-compromised mice. Together, these results indicate that loss of p53 alone is sufficient to induce primary liver cancer with bilineal differentiation originating from chromosomal instable cultured liver progenitor cells or hepatocytes. Conclusions: The study shows that p53-dependent checkpoints inhibit transformation of liver progenitor cells and hepatocytes involving p21-independent mechanisms.

ORGANISM(S): Mus musculus

PROVIDER: GSE34760 | GEO | 2011/12/29

SECONDARY ACCESSION(S): PRJNA150383

REPOSITORIES: GEO

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p53 deletion induces liver carcinoma with bilineal differentiation

Project description:Background and Aims: p53 can limit the self-renewal of stem cells from various tissues. Experimental evidence suggests that deletion of p53 can cooperate with other oncogenic events to induce aberrant self-renewal and transformation of progenitor cells. It is not known whether p53 deletion alone can lead to liver tumor formation. Methods: We used AlfpCre mice for liver-specific deletion of Trp53 in a conditional knockout mouse model to analyze liver carcinogenesis. Results: Here, we show that liver-specific deletion of p53 in mice consistently induces formation of liver carcinoma depicting bilineal differentiation. Freshly isolated p53-/- liver progenitor cells and hepatocytes exhibit chromosomal imbalances and an enhanced clonogenic capacity compared to p53-positive cells or p21-deficient cells. Primary cultures of hepatocytes and liver progenitor cells from p53-/- mice formed tumors with bilineal differentiation when transplanted into immuno-compromised mice. Together, these results indicate that loss of p53 alone is sufficient to induce primary liver cancer with bilineal differentiation originating from chromosomal instable cultured liver progenitor cells or hepatocytes. Conclusions: The study shows that p53-dependent checkpoints inhibit transformation of liver progenitor cells and hepatocytes involving p21-independent mechanisms. Liver tumors derived from Trp53 KO mice, liver tumors from DEN-treated wildtype mice, Trp53 KO liver and wildtype liver were isolated and RNA was extracted. Agilent-026655 Mouse 4x44K v2 arrays were used.

2011-12-29 | E-GEOD-34760 | biostudies-arrayexpress

Epigenetic stress responses induce muscle stem cell aging by Hoxa9 developmental signals [microarray]

Project description:Background and Aims: Analysis of aging-induced impairments in satellite cells (SCs) – the stem cells of skeletal muscle that are required for its regeneration. Hox genes are known to control stem cell function and development of various tissues. Methods: We used AlfpCre mice for liver specific deletion of Trp53 in a conditional knockout mouse model to analyze liver carcinogenesis. Results: Here, we show that liver-specific deletion of p53 in mice consistently induces formation of liver carcinoma depicting bilineal differentiation. Freshly isolated p53-/- liver progenitor cells and hepatocytes exhibit chromosomal imbalances and an enhanced clonogenic capacity compared to p53-positive cells or p21-deficient cells. Primary cultures of hepatocytes and liver progenitor cells from p53-/- mice formed tumors with bilineal differentiation when transplanted into immuno-compromised mice. Together, these results indicate that loss of p53 alone is sufficient to induce primary liver cancer with bilineal differentiation originating from chromosomal instable cultured liver progenitor cells or hepatocytes. Conclusions: The study shows that p53-dependent checkpoints inhibit transformation of liver progenitor cells and hepatocytes involving p21-independent mechanisms. In this study the function of the Hoxa9 was analyzed in murine satellite cells.

2016-11-30 | GSE87811 | GEO

Mus musculus

Project description:p53 deletion induces liver carcinoma with bilineal differentiation

| PRJNA150383 | ENA

aCGH analysis of liver tumors generated in C57BL/6J mice with a liver specific loss of Trp53-/- [Agilent-024427]

Project description:Background and aims: P53 limits the self-renewal of stem cells from various tissue. A Loss of p53 in combination with other oncogenic events results in aberrant self-renewal and transformation of progenitor cells. Here, we investigated whether a loss of p53 as a single genetic lesion is sufficient to induce liver tumor formation. Methods: AlfpCre mice were crossed with Trp53 conditional knockout mice to achieve a liver-specific loss of Trp53. Results: The liver-specific loss of Trp53 results in liver tumor formation. A high percentage of the tumors showed a mixed differentiation of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Conclusion: The liver-specific deletion of Trp53 is sufficient to induce liver tumor formation.

2021-01-22 | GSE156253 | GEO

aCGH analysis of liver tumors generated in C57BL/6J mice with a liver specific loss of Trp53-/- [Agilent-027411]

2021-01-22 | GSE156252 | GEO

aCGH analysis of liver tumors generated in FAH-/- Trp53-/- mice, a mouse model of metabolic liver injury

Project description:Background and aims: A coordinated stress and regenerative response is important following hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the CHK2/ p53/ p21 pathway in a murine model of metabolic liver injury. Methods: NTBC was reduced or withdrawn in Fah / mice lacking Chk2, p53 or p21, and survival, tumor development, liver injury and regeneration were analyzed. Partial hepatectomies were performed and mice were challenged with the Fas-antibody Jo2. Results: In a model of metabolic liver injury, loss of p53, but not of Chk2, impairs the oxidative stress re-sponse and aggravates liver damage, indicative of a direct p53-dependent protective effect on hepatocytes. Cell cycle control during chronic liver injury critically depends on the presence of both p53 and its downstream effector p21. In p53-deficient hepatocytes, unchecked proliferation occurs despite a strong induction of p21, revealing a complex interdependency between p21 and p53. The increased regenerative potential in the absence of p53 cannot fully compensate the surplus injury and is not sufficient to promote survival. Despite the different phenotypes as-sociated with the loss of individual components of the DNA damage response, gene expression patterns are dominated by the severity of liver injury, but reflect distinct effects of p53 on prolif-eration and the anti-oxidative stress response. Conclusion: Characteristic phenotypes result from the genetic abrogation of individual components of the DNA damage response cascade in a liver injury model. The extent to which loss of gene function can be compensated, or affects injury and proliferation, depends on the level at which the cas-cade is interrupted.

2021-04-02 | GSE156251 | GEO

Disruption of the DNA damage pathway at different levels results in distinct phenotypes in a murine liver injury model

2020-12-31 | GSE156852 | GEO

aCGH analysis of liver tumors generated in FAH-/- mice, a mouse model of metabolic liver injury

Project description:Background and aims: A coordinated stress and regenerative response is important following hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the CHK2/ p53/ p21 pathway in a murine model of metabolic liver injury. Methods: NTBC was reduced or withdrawn in FAH-/- mice lacking Chk2, p53 or p21, and survival, tumor development, liver injury and regeneration were analyzed. Partial hepatectomies were performed and mice were challenged with the Fas-antibody Jo2. Results: In a model of metabolic liver injury, loss of p53, but not of Chk2, impairs the oxidative stress re-sponse and aggravates liver damage, indicative of a direct p53-dependent protective effect on hepatocytes. Cell cycle control during chronic liver injury critically depends on the presence of both p53 and its downstream effector p21. In p53-deficient hepatocytes, unchecked proliferation occurs despite a strong induction of p21, revealing a complex interdependency between p21 and p53. The increased regenerative potential in the absence of p53 cannot fully compensate the surplus injury and is not sufficient to promote survival. Despite the different phenotypes as-sociated with the loss of individual components of the DNA damage response, gene expression patterns are dominated by the severity of liver injury, but reflect distinct effects of p53 on prolif-eration and the anti-oxidative stress response. Conclusion: Characteristic phenotypes result from the genetic abrogation of individual components of the DNA damage response cascade in a liver injury model. The extent to which loss of gene function can be compensated, or affects injury and proliferation, depends on the level at which the cas-cade is interrupted.

2021-04-02 | GSE156981 | GEO

Intestinal ablation of CKIalpha highlights invasiveness control

Project description:Wnt signaling, which drives the rapid self-renewal of the gut epithelium is causally associated with intestinal neoplasia. Here we show that CKIalpha is a activation depends on p53 and p21Waf1/Cip1: CKIÎ± ablation provokes activation of p53 and p21, which assume a pivotal role in suppressing invasive cancer. Dual loss of CKIalpha and either p53 or p21 results in rapid, rampant malignant signature denoted p53supinv (p53-suppressed invasiveness) that is conditionally induction of invasiveness. Like invasiveness control, the transcriptional suppression of p53supinv genes is largely mediated by p21, independently of cell cycle control, representing a novel tumor suppressor function of wild-type p53. 13 arrays of mice entrocytes herto or homozygot for gut specific KO of CKI alpha. Crossed with p53 or p21 KO mice.

2010-10-23 | E-GEOD-24760 | biostudies-arrayexpress

Oval cells from DDB1 mutant mouse

Project description:Quiescent hepatic stem cells (HSCs) can be activated when hepatocyte proliferation is compromised. Chemical injury rodent models have been widely used to study the locazation, biomarkers, and signaling pathways in HSCs, but these models usually exhibit severe promiscuous toxicity and fail to distinguish damaged and non-damaged cells. Our goal is to establish new animal models to overcome these limitations, thereby providing new insights into HSC biology and application. We generated mutant mice with constitutive or inducible deletion of Damaged DNA Binding protein 1 (DDB1), an E3 ubiquitin ligase, in hepatocytes. We show that deletion of DDB1 abolishes self-renewal capacity of mouse hepatocytes in vivo, leading to compensatory activation and proliferation of DDB1-expressing OCs. Importantly, the DDB1 mutant mice exhibit very minor liver damage, compared to a chemical injury model. Microarray analysis reveals several previously unrecognized markers, enriched in oval cells. This genetic model in which irreversible inhibition of hepatocyte duplication results in HSC-driven liver regeneration. The DDB1 mutant mice can be broadly applied to studies of HSC differentiation, HSC niche and HSCs as origin of liver cancer. Total RNA obtained from isolated EpCAM+ cells from DDB1 mutant mice compared to wild type hepatocytes

2012-01-01 | E-GEOD-31588 | biostudies-arrayexpress

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