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Évry, France

Cairo S.,XenTech | Armengol C.,CIBER ISCIII | Buendia M.A.,Institute Pasteur Paris
Frontiers in Bioscience - Elite | Year: 2012

Hepatoblastoma (HB) is the most common type of pediatric liver cancer. This tumor is thought to derive from hepatic progenitor cells that are arrested at various stages of liver development, as illustrated by a variety of histologic subtypes. Recent genomic studies have led to better understand the molecular pathogenesis of HB, to point out the crucial roles of the Wnt Myc signaling pathways in malignant transformation of liver progenitor cells. Molecular classification of HB based on genomewide studies, as well as identification of reliable diagnostic prognostic markers, open the way to the development of new personalized targeted therapies for the management of aggressive lethal childhood tumors.

Eichenmuller M.,Ludwig Maximilians University of Munich | Trippel F.,Ludwig Maximilians University of Munich | Kreuder M.,Ludwig Maximilians University of Munich | Beck A.,Ludwig Maximilians University of Munich | And 10 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Hepatoblastoma (HB) is the most common childhood liver cancer and occasionally presents with histological and clinical features reminiscent of hepatocellular carcinoma (HCC). Identification of molecular mechanisms that drive the neoplastic continuation towards more aggressive HCC phenotypes may help to guide the new stage of targeted therapies. Methods We performed comprehensive studies on genetic and chromosomal alterations as well as candidate gene function and their clinical relevance. Results Whole-exome sequencing identified HB as a genetically very simple tumour (2.9 mutations per tumour) with recurrent mutations in ß-catenin (CTNNB1) (12/15 cases) and the transcription factor NFE2L2 (2/15 cases). Their HCC-like progenies share the common CTNNB1 mutation, but additionally exhibit a significantly increased mutation number and chromosomal instability due to deletions of the genome guardians RAD17 and TP53, accompanied by telomerase reverse-transcriptase (TERT) promoter mutations. Targeted genotyping of 33 primary tumours and cell lines revealed CTNNB1, NFE2L2, and TERT mutations in 72.5%, 9.8%, and 5.9% of cases, respectively. All NFE2L2 mutations affected residues of the NFE2L2 protein that are recognized by the KEAP1/CUL3 complex for proteasomal degradation. Consequently, cells transfected with mutant NFE2L2 were insensitive to KEAP1-mediated downregulation of NFE2L2 signalling. Clinically, overexpression of the NFE2L2 target gene NQO1 in tumours was significantly associated with metastasis, vascular invasion, the adverse prognostic C2 gene signature, as well as poor outcome. Conclusions Our study demonstrates the importance of CTNNB1 mutations and NFE2L2-KEAP1 pathway activation in HB development and defines loss of genomic stability and TERT promoter mutations as prominent characteristics of aggressive HB with HCC features. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Tebbi A.,Institute Pasteur Paris | Levillayer F.,Institute Pasteur Paris | Jouvion G.,Institute Pasteur Paris | Fiette L.,Institute Pasteur Paris | And 10 more authors.
Carcinogenesis | Year: 2016

Multidrug resistance 2 (Mdr2), also called adenosine triphosphate-binding cassette B4 (ABCB4), is the transporter of phosphatidylcholine (PC) at the canalicular membrane of mouse hepatocytes, which plays an essential role for bile formation. Mutations in human homologue MDR3 are associated with several liver diseases. Knockout of Mdr2 results in hepatic inflammation, liver fibrosis and hepatocellular carcinoma (HCC). Whereas the pathogenesis in Mdr2-/- mice has been largely attributed to the toxicity of bile acids due to the absence of PC in the bile, the question of whether Mdr2 deficiency per se perturbs biological functions in the cell has been poorly addressed. As Mdr2 is expressed in many cell types, we used mouse embryonic fibroblasts (MEF) derived from Mdr2-/- embryos to show that deficiency of Mdr2 increases reactive oxygen species accumulation, lipid peroxidation and DNA damage. We found that Mdr2-/- MEFs undergo spontaneous transformation and that Mdr2-/- mice are more susceptible to chemical carcinogen-induced intestinal tumorigenesis. Microarray analysis in Mdr2-/- MEFs and cap analysis of gene expression in Mdr2-/- HCCs revealed extensively deregulated genes involved in oxidation reduction, fatty acid metabolism and lipid biosynthesis. Our findings imply a close link between Mdr2-/--associated tumorigenesis and perturbation of these biological processes and suggest potential extrahepatic functions of Mdr2/MDR3. © The Author 2015. Published by Oxford University Press.

Cairo S.,XenTech | Buendia M.A.,University Paris - Sud
Journal of Hepatology | Year: 2012

Hepatocyte nuclear factor 4a (HNF4a) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4a initiates hepatocellular transformation through a microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that,once this circuit is activated, it maintains suppression of HNF4a and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4a circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.

Bikeye S.-N.N.,French Institute of Health and Medical Research | Colin C.,Aix - Marseille University | Marie Y.,French Institute of Health and Medical Research | Vampouille R.,University Pierre and Marie Curie | And 10 more authors.
Cancer Cell International | Year: 2010

Background: ASPM (Abnormal Spindle-like Microcephaly associated) over-expression was recently implicated in the development of malignant gliomas.Results: To better characterize the involvement of ASPM in gliomas, we investigated the mRNA expression in 175 samples, including 8 WHO Grade II, 75 WHO Grade III and 92 WHO Grade IV tumors. Aspm expression was strongly correlated with tumor grade and increased at recurrence when compared to the initial lesion, whatever the initial grade of the primary tumor. ASPM expression also increased over serial passages in gliomaspheres in vitro and in mouse xenografts in vivo. Lentivirus-mediated shRNA silencing of ASPM resulted in dramatic proliferation arrest and cell death in two different gliomasphere models.Conclusion: These data suggest that ASPM is involved in the malignant progression of gliomas, possibly through expansion of a cancer stem cell compartment, and is an attractive therapeutic target in glioblastoma multiforme. © 2010 Bikeye et al; licensee BioMed Central Ltd.

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