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1.
J Clin Invest ; 126(8): 2955-69, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-27454291

RESUMEN

E2F-mediated transcriptional repression of cell cycle-dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8's tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8's DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Factor de Transcripción E2F7/metabolismo , Neoplasias Hepáticas/metabolismo , Hígado/crecimiento & desarrollo , Proteínas Represoras/metabolismo , Alelos , Animales , Biopsia , Proliferación Celular , Supervivencia Celular , ADN/análisis , Factor de Transcripción E2F7/genética , Femenino , Eliminación de Gen , Genotipo , Hepatocitos/citología , Humanos , Hígado/fisiología , Masculino , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Unión Proteica , Dominios Proteicos , Proteínas Represoras/genética , Análisis de Secuencia de ARN , Transducción de Señal
2.
Oncotarget ; 7(34): 54662-54675, 2016 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-27323406

RESUMEN

The long term prognosis of liver cancer patients remains unsatisfactory because of cancer recurrence after surgical interventions, particularly in patients with viral infections. Since hepatitis B and C viral proteins lead to inactivation of the tumor suppressors p53 and Retinoblastoma (Rb), we hypothesize that surgery in the context of p53/Rb inactivation initiate de novo tumorigenesis.We, therefore, generated transgenic mice with hepatocyte and cholangiocyte/liver progenitor cell (LPC)-specific deletion of p53 and Rb, by interbreeding conditional p53/Rb knockout mice with either Albumin-cre or Cytokeratin-19-cre transgenic mice.We show that liver cancer develops at the necrotic injury site after surgical resection or radiofrequency ablation in p53/Rb deficient livers. Cancer initiation occurs as a result of specific migration, expansion and transformation of cytokeratin-19+-liver (CK-19+) cells. At the injury site migrating CK-19+ cells formed small bile ducts and adjacent cells strongly expressed the transforming growth factor ß (TGFß). Isolated cytokeratin-19+ cells deficient for p53/Rb were resistant against hypoxia and TGFß-mediated growth inhibition. CK-19+ specific deletion of p53/Rb verified that carcinomas at the injury site originates from cholangiocytes or liver progenitor cells.These findings suggest that human liver patients with hepatitis B and C viral infection or with mutations for p53 and Rb are at high risk to develop tumors at the surgical intervention site.


Asunto(s)
Transformación Celular Neoplásica/genética , Queratina-19/genética , Neoplasias Hepáticas/genética , Hígado/metabolismo , Proteína de Retinoblastoma/genética , Proteína p53 Supresora de Tumor/genética , Animales , Ablación por Catéter/efectos adversos , Ablación por Catéter/métodos , Proliferación Celular/genética , Transformación Celular Neoplásica/metabolismo , Hepatectomía/efectos adversos , Hepatectomía/métodos , Hepatocitos/metabolismo , Humanos , Queratina-19/metabolismo , Hígado/patología , Hígado/cirugía , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteína de Retinoblastoma/deficiencia , Técnicas de Cultivo de Tejidos , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Proteína p53 Supresora de Tumor/deficiencia
3.
PLoS One ; 11(3): e0150064, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26967735

RESUMEN

The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC is metabolized mainly by cytochrome P450 (Cyp)3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Piridinas/farmacocinética , Proteína de Retinoblastoma/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Protoporfirinas/metabolismo , Piridinas/toxicidad , Proteína de Retinoblastoma/genética , Proteína p53 Supresora de Tumor/genética
4.
Stem Cells Transl Med ; 5(3): 325-30, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26798060

RESUMEN

Organoids are three-dimensional culture systems in which adult stem cells and their progeny grow and represent the native physiology of the cells in vivo. Organoids have been successfully derived from several organ systems in both animal models and human patients. Organoids have been used for fundamental research, disease modeling, drug testing, and transplantation. In this review, we summarize the applications of liver-derived organoids and discuss their potential. It is likely that organoids will provide an invaluable tool to unravel disease mechanisms, design novel (personalized) treatment strategies, and generate autologous stem cells for gene editing and transplantation purposes.


Asunto(s)
Técnicas de Cultivo de Célula , Hígado/citología , Organoides/citología , Células Madre/citología , Adulto , Animales , Humanos , Hígado/metabolismo , Trasplante de Células Madre
5.
Stem Cell Reports ; 5(5): 895-907, 2015 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-26455412

RESUMEN

The recent development of 3D-liver stem cell cultures (hepatic organoids) opens up new avenues for gene and/or stem cell therapy to treat liver disease. To test safety and efficacy, a relevant large animal model is essential but not yet established. Because of its shared pathologies and disease pathways, the dog is considered the best model for human liver disease. Here we report the establishment of a long-term canine hepatic organoid culture allowing undifferentiated expansion of progenitor cells that can be differentiated toward functional hepatocytes. We show that cultures can be initiated from fresh and frozen liver tissues using Tru-Cut or fine-needle biopsies. The use of Wnt agonists proved important for canine organoid proliferation and inhibition of differentiation. Finally, we demonstrate that successful gene supplementation in hepatic organoids of COMMD1-deficient dogs restores function and can be an effective means to cure copper storage disease.


Asunto(s)
Células Madre Adultas/metabolismo , Terapia Genética/métodos , Hepatocitos/metabolismo , Degeneración Hepatolenticular/terapia , Proteínas Adaptadoras Transductoras de Señales/genética , Células Madre Adultas/citología , Animales , Diferenciación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Perros , Hepatocitos/citología , Degeneración Hepatolenticular/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Proteínas Wnt/agonistas , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
6.
Nat Cell Biol ; 14(11): 1181-91, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23064264

RESUMEN

Polyploidization is observed in all mammalian species and is a characteristic feature of hepatocytes, but its molecular mechanism and biological significance are unknown. Hepatocyte polyploidization in rodents occurs through incomplete cytokinesis, starts after weaning and increases with age. Here, we show in mice that atypical E2F8 is induced after weaning and required for hepatocyte binucleation and polyploidization. A deficiency in E2f8 led to an increase in the expression level of E2F target genes promoting cytokinesis and thereby preventing polyploidization. In contrast, loss of E2f1 enhanced polyploidization and suppressed the polyploidization defect of hepatocytes deficient for atypical E2Fs. In addition, E2F8 and E2F1 were found on the same subset of target promoters. Contrary to the long-standing hypothesis that polyploidization indicates terminal differentiation and senescence, we show that prevention of polyploidization through inactivation of atypical E2Fs has, surprisingly, no impact on liver differentiation, zonation, metabolism and regeneration. Together, these results identify E2F8 as a repressor and E2F1 as an activator of a transcriptional network controlling polyploidization in mammalian cells.


Asunto(s)
Factor de Transcripción E2F1/metabolismo , Poliploidía , Proteínas Represoras/metabolismo , Animales , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F7/genética , Factor de Transcripción E2F7/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Hígado/citología , Hígado/metabolismo , Ratones , Ratones Noqueados , Proteínas Represoras/genética
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