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Heat shock response associated with hepatocarcinogenesis in a murine model of hereditary tyrosinemia type I.

ABSTRACT: Hereditary Tyrosinemia type 1 (HT1) is a metabolic liver disease caused by genetic defects of fumarylacetoacetate hydrolase (FAH), an enzyme necessary to complete the breakdown of tyrosine. The severe hepatic dysfunction caused by the lack of this enzyme is prevented by the therapeutic use of NTBC (2-[2-nitro-4-(trifluoromethyl)benzoyl] cyclohexane-1,3-dione). However despite the treatment, chronic hepatopathy and development of hepatocellular carcinoma (HCC) are still observed in some HT1 patients. Growing evidence show the important role of heat shock proteins (HSPs) in many cellular processes and their involvement in pathological diseases including cancer. Their survival-promoting effect by modulation of the apoptotic machinery is often correlated with poor prognosis and resistance to therapy in a number of cancers. Here, we sought to gain insight into the pathophysiological mechanisms associated with liver dysfunction and tumor development in a murine model of HT1. Differential gene expression patterns in livers of mice under HT1 stress, induced by drug retrieval, have shown deregulation of stress and cell death resistance genes. Among them, genes coding for HSPB and HSPA members, and for anti-apoptotic BCL-2 related mitochondrial proteins were associated with the hepatocarcinogenetic process. Our data highlight the variation of stress pathways related to HT1 hepatocarcinogenesis suggesting the role of HSPs in rendering tyrosinemia-affected liver susceptible to the development of HCC.

SUBMITTER: Angileri F

PROVIDER: S-EPMC4074813 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Heat shock response associated with hepatocarcinogenesis in a murine model of hereditary tyrosinemia type I.

Angileri Francesca F Morrow Geneviève G Roy Vincent V Orejuela Diana D Tanguay Robert M RM

Cancers 20140423 2

Hereditary Tyrosinemia type 1 (HT1) is a metabolic liver disease caused by genetic defects of fumarylacetoacetate hydrolase (FAH), an enzyme necessary to complete the breakdown of tyrosine. The severe hepatic dysfunction caused by the lack of this enzyme is prevented by the therapeutic use of NTBC (2-[2-nitro-4-(trifluoromethyl)benzoyl] cyclohexane-1,3-dione). However despite the treatment, chronic hepatopathy and development of hepatocellular carcinoma (HCC) are still observed in some HT1 patie ...[more]

PMID: 24762634

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Project description:Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). It has been previously shown that ex vivo hepatocyte-directed gene therapy using an integrating lentiviral vector to replace the defective Fah gene can cure liver disease in small- and large-animal models of HT1. This study hypothesized that ex vivo hepatocyte-directed gene editing using CRISPR/Cas9 could be used to correct a mouse model of HT1, in which a single point mutation results in loss of FAH function. To achieve high transduction efficiencies of primary hepatocytes, this study utilized a lentiviral vector (LV) to deliver both the Streptococcus pyogenes Cas9 nuclease and target guide RNA (LV-Cas9) and an adeno-associated virus (AAV) vector to deliver a 1.2 kb homology template (AAV-HT). Cells were isolated from Fah-/- mice and cultured in the presence of LV and AAV vectors. Transduction of cells with LV-Cas9 induced significant indels at the target locus, and correction of the point mutation in Fah-/- cells ex vivo using AAV-HT was completely dependent on LV-Cas9. Next, hepatocytes transduced ex vivo by LV-Cas9 and AAV-HT were transplanted into syngeneic Fah-/- mice that had undergone a two-thirds partial hepatectomy or sham hepatectomy. Mice were cycled on/off the protective drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) to stimulate expansion of corrected cells. All transplanted mice became weight stable off NTBC. However, a significant improvement was observed in weight stability off NTBC in animals that received partial hepatectomy. After 6 months, mice were euthanized, and thorough biochemical and histological examinations were performed. Biochemical markers of liver injury were significantly improved over non-transplanted controls. Histological examination of mice revealed normal tissue architecture, while immunohistochemistry showed robust repopulation of recipient animals with FAH+ cells. In summary, this is the first report of ex vivo hepatocyte-directed gene repair using CRISPR/Cas9 to demonstrate curative therapy in an animal model of liver disease.

Dataset Information

Heat shock response associated with hepatocarcinogenesis in a murine model of hereditary tyrosinemia type I.

Publications

Heat shock response associated with hepatocarcinogenesis in a murine model of hereditary tyrosinemia type I.

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