Mouse Models of Hepatocellular Carcinoma

Fausto, Nelson; Campbell, Jean S.

doi:10.1055/s-0030-1247135

Cited by 85 publications

(90 citation statements)

References 53 publications

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“…To test directly whether NCOA2 functions as a putative tumor suppressor in vivo, we treated previously described Ncoa2 +/+ and Ncoa2 −/− mice (24) with the chemical carcinogen DEN. Exposure to DEN causes liver damage and hepatocellular carcinogenesis in mice (25,26). We chose to analyze males because DEN-induced tumorigenesis is known to be more effective in males than in females and because males were analyzed in the original transposon screen.…”

Section: Sb Insertions In Lymphomas Are Distinct From Liver Tumor Insmentioning

confidence: 99%

A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

O’Donnell

Keng

York

et al. 2012

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

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The Sleeping Beauty (SB) transposon mutagenesis system is a powerful tool that facilitates the discovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations that cooperate with MYC, one of the most commonly dysregulated genes in human malignancy. We performed a forward genetic screen with a mouse model of MYC-induced liver cancer using SBmediated mutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci that contribute to accelerated tumor development. RNAi-mediated knockdown in a liver progenitor cell line further validate three of these genes, Ncoa2/ Src-2, Zfx, and Dtnb, as tumor suppressors in liver cancer. Moreover, deletion of Ncoa2/Src-2 in mice predisposes to diethylnitrosamineinduced liver tumorigenesis. These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesis and therefore may provide targets for cancer therapy. T ransposable elements (TEs) are powerful genetic tools that are widely used in insertional mutagenesis screens because of the facile identification of transposon-induced mutations. The application of transposon-based approaches to cancer gene identification provides opportunities to study the consequences of specific mutations in the context of tumor cell initiation, progression, and maintenance in well-defined, genetically engineered mouse models. Sleeping Beauty (SB), a member of the Tc1/mariner superfamily of DNA transposons, is highly active in mammalian cells (1). A growing body of evidence has demonstrated that SB is an efficient tool for cancer gene discovery when used in forward genetic screens in mice (2, 3).The SB system is based on the use of two transgenic mouse lines, one harboring a transposase and the other with a concatemerized mutagenic transposon containing sequences that can disrupt gene function through either gain-of-function or loss-offunction mechanisms. The transposase binds to the transposon ends and catalyzes its mobilization to new sites. The effect of ubiquitous transposition in mice is the development of T-cell leukemia and brain tumors (3, 4). In contrast, restricted expression of SB transposase accelerates fibrosarcoma development in p19 Arf −/− mice (2).Recently, this approach has been modified through the conditional activation of the SB transposase in specific tissues using Cre/LoxP technology (5, 6). In one of these studies, an SB screen identified 19 genes that accelerate liver cancer induced by expression of a dominant-negative Trp53 transgene. However, the SB system has not been used previously to identify genes that cooperate with oncogenes that initiate liver tumorigenesis.Hepatocellular carcinoma (HCC) is the fifth most common solid tumor worldwide and is the third leading cause of death from cancer (7,8). In the majority of cases, it occurs in a setting of chronic inflammation or cirrhosis. Although numerous genomic alterations have been documented in liver cancer, the key genetic alterations that drive hepatocellular transforma...

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Section: Sb Insertions In Lymphomas Are Distinct From Liver Tumor Insmentioning

confidence: 99%

A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

O’Donnell

Keng

York

et al. 2012

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

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“…Many of these factors involve exposure to carcinogenic compounds, such as N-nitrosamines. N-nitrosamines have carcinogenic, mutagenic and teratogenic properties and can be found in smoked meat and fish products, milk and dairy products, soft drinks, alcoholic beverages and cigarette smoke (Dutra et al, 2007;Fausto and Campbell, 2010;Inami et al, 2010;Kartik et al, 2010). These compounds are structurally divided in N-nitrosamides and N-nitrosodialkylamines, both with alkylation capability to induce DNA damage.…”

Section: Introductionmentioning

confidence: 99%

“…Contrary to N-nitrosamides, N-nitrosodialkylamines require metabolic activation (-hydroxylation), mediated by cytochrome P450 enzymes, in order to induce DNA damage. N-diethylnitrosamine (DEN) is a genotoxic, carcinogenic nitrosamine having its place among N-nitrosodialkylamines (Dutra et al, 2007;Fausto and Campbell, 2010;Heindryckx et al, 2009;Inami et al, 2010;Verna et al, 1996). According to Inami et al (2010), spontaneous decomposition of -hydroxynitrosamines generates aldehydes and alkanediazohy-droxides, followed by the production of alkyldiazonium ions, which alkylate DNA bases.…”

Section: Introductionmentioning

confidence: 99%

N-diethylnitrosamine mouse hepatotoxicity: Time-related effects on histology and oxidative stress

Santos

Colaço

Costa

et al. 2014

Experimental and Toxicologic Pathology

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Animal models, namely mice, have been used to study chemically induced carcinogenesis due to their similarity to the histological and genetic features of human patients. Hepatocellular carcinoma (HCC) is a common malignancy with poor clinical outcome. The high incidence of HCC might be related to expo-sure to known risk factors, including carcinogenic compounds, such as N-nitrosamines, which cause DNA damage. N-nitrosamines affect cell mitochondrial metabolism, disturbing the balance between reactive oxygen species (ROS) and antioxidants, causing oxidative stress and DNA damage, potentially leading to carcinogenesis. This work addresses the progressive histological changes in the liver of N-diethylnitrosamine (DEN)-exposed mice and its correlation with oxidative stress.Male ICR mice were randomly divided into five DEN-exposed and five matched control groups. DEN was IP administered, once a week, for eight consecutive weeks.2 Samples were taken 18 h after the last DEN injection (8 weeks post-exposure). The following sampling occurred at weeks 15th, 22nd, 29th and 36th after the first DEN injection. DEN resulted in early toxic lesions and, from week 29 onwards, in progressive proliferative lesions. Between 15 and 29 weeks, DEN-exposed animals showed significant changes in hepatic antioxidant (glutathione, glutathione reductase, and catalase) status (p < 0.05) compared with controls. These results point to an association between increased DEN-induced oxidative stress and the early histopathological alterations, suggesting that DEN disrupted the antioxidant defense mechanism, thereby triggering liver carcinogenesis.

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“…DEN, a well known hepatocarcinogen, is widely used in mouse liver cancer models (Fausto and Campbell, 2010). In ESCs treated with DEN, GPC-3 expression was increased, however, its expression was also localized at cell membrane.…”

Section: Discussionmentioning

confidence: 99%

Expression of Glypican-3 in Mouse Embryo Stem Cells and its Derived Hepatic Lineage Cells Treated with Diethylnitrosamine in vitro

Kim

Kang²

2013

Asian Pacific Journal of Cancer Prevention

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To clarify the role of stem cells in hepatocarcinogenesis, glypican-3 (GPC-3) and E-cadherin expression was investigated in embryonic cell lineages. Mouse embryonic stem cells (ESCs), hepatic progenitor cells (HPCs) and hepatocyte like cells (HCs), representing 0, 22 and 40 days of differentiation, respectively, were treated in vitro with diethylnitrosamine (DEN) at four doses (0, 1, 5 and 15 mM; G1, G2, G3 and G4, respectively) for 24 h and GPC-3 and E-cadherin expression was examined by relative quantitative real-time PCR and immunocytochemistry. GPC-3 mRNA expression was significantly different for G4 at day 0 (p<0.001) and for G4 at day 22 (p<0.01) compared with the control (G1). E-cadherin mRNA expression was significantly different for G3 and G4 at day 0 (p<0.05 and p<0.001, respectively), for G2 and G4 (p<0.05 and p<0.001, respectively) at day 22 and for G2 and G4 (p<0.01 and p<0.001, respectively) at day 40 compared with G1. Immunofluorescence staining for GPC-3 showed a membranous and/or granular expression in cytoplasm of ESCs and HPCs and granular and/or diffuse expression in cytoplasm of HCs, which were also stained by E-cadherin. DEN treatment increased GPC-3 expression in ESCs, HPCs and HCs, with increase of E-cadherin expression. Taken together, the expression of GPC-3 was altered by DEN treatment. However, its expression pattern was different at the stage of embryo stem cells and its derived hepatic lineage cells. This suggests that GPC-3 expression may be modulated in the progeny of stem cells during their differentiation toward hepatocytes, associated with E-cadherin expression.

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Mouse Models of Hepatocellular Carcinoma

Cited by 85 publications

References 53 publications

A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

N-diethylnitrosamine mouse hepatotoxicity: Time-related effects on histology and oxidative stress

Expression of Glypican-3 in Mouse Embryo Stem Cells and its Derived Hepatic Lineage Cells Treated with Diethylnitrosamine in vitro

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