Accueil > CITI Department > Epigenetics, microenvironment and liver cancer
Epigenetics, microenvironment and liver cancer
Objectives
Our team aims to utilize cutting edge innovative technologies and to link high technology to clinical application by extensive validation of the new findings in patient samples from relevant clinical settings.
Our team success and its translational value will very much depend on the access to liver samples from well-defined categories of patients. This will be achieved through the collaboration with a vast net of leading clinical groups in HBV and HCC research in Italy and France.
Altogether, our research efforts will generate new knowledge and provide new insights on the molecular pathogenesis of virus-related HCCs but will also, hopefully, provide data for the rationale use of anti-Ezh2/PRC2 in HCC treatment and lead to the development of biomarkers for early diagnosis, prognostication and treatment allocation of liver cancer patients.
Projects
HCC is one of the most frequent tumors worldwide and due to its poor prognosis, is the 2nd cause of cancer death worldwide. In Europe, HCC incidence and mortality rates are of 65,000 and 60,240 cases in Europe, respectively.
HCC development is driven by multiple viruses (HBV, HCV) and chronic metabolic alterations leading to chronic inflammation, DNA damage, epigenetic and genetic changes that affect both “common” and “etiology specific” oncogenic pathways. Importantly, whereas mutations and chromosomal aberrations, with the only exception of TERT promoter mutation, have been consistently found in tumor tissues, deregulation of signaling pathways and epigenetic changes (DNA methylation, post-translational histone modifications and noncoding RNA-mediated silencing pathways) are also detected early in the natural history of HCC development, at the stage of chronic hepatitis, cirrhosis or dysplastic nodules. Epigenetic changes include, occur early in the development of HCC.
The EpiHep team investigates the epigenetic changes that precede and accompany HCC development and progression mainly, but not exclusively, in the setting of HBV chronic liver diseases.
Specific research projects aim to:
- Define the contribution of the viral protein HBx and HBc in HBV pathogenicity, liver tumors development and progression;
- Study the expression profiles of exhausted antigen specific CD8 lymphocytes in chronic HBV carriers and HBV-related HCCs and test new pharmacological correction strategies;
- Identify the gene network controlled by the PRC2/Ezh2 complex in normal and neoplastic liver cells and to investigate the functional consequences of Ezh2 genetic knockdown and pharmacological manipulation;
- Identify genes and ncRNAs co-regulated by IL6/STAT3 and the PRC2 complex in HBV, HCV and NASH-related cancers and investigate their modulation by AMPK and metformin.
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Massimo Levrero
Bâtiment Inserm
151 Cours Albert Thomas
69424 Lyon Cedex 03massimo.levrero@inserm.fr
04 72 68 19 79
04 72 68 19 70 (secretariat)
Members
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MOHKAM Kayvan
Professeur Universitaire - Praticien Hospitalier UCBL/HCL - Equipe Levrero
Publications
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GNS561, a new autophagy inhibitor active against cancer stem cells in hepatocellular carcinoma and hepatic metastasis from colorectal cancer
Brun S, Pascussi JM, Gifu EP, Bestion E, Macek-Jilkova Z, Wang G, Bassissi F, Mezouar S, Courcambeck J, Merle P, Decaens T, Pannequin J, Halfon P, Caron de Fromentel C Journal of Cancer
Impact of 2016 Enhanced Recovery After Surgery (ERAS) Recommendations on Outcomes after Hepatectomy in Cirrhotic and Non-Cirrhotic PatientsLunel T, Mohkam K, Merle P, Bonnet A, Gazon M, Dumont PN, Ducerf C, Mabrut JY, Lesurtel M World Journal of Surgery
The lncRNAs in HBV-Related HCCs: Targeting Chromatin Dynamics and BeyondAlfano V, Zeisel MB, Levrero M, Guerrieri F Cancers
Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trialGalle PR, Finn RS, Qin S, Ikeda M, Zhu AX, Kim TY, Kudo M, Breder V, Merle P, Kaseb A, Li D, Mulla S, Verret W, Xu DZ, Hernandez S, Ding B, Liu J, Huang C, Lim HY, Cheng AL, Ducreux M Lancet Oncology
Host Epigenetic Alterations and Hepatitis B Virus-Associated Hepatocellular CarcinomaZeisel MB, Guerrieri F, Levrero M Journal of Clinical Medicine
RNA helicase DDX5 enables STAT1 mRNA translation and interferon signalling in hepatitis B virus replicating hepatocytesSun J, Wu G, Pastor F, Rahman N, Wang WH, Zhang Z, Merle P, Hui L, Salvetti A, Durantel D, Yang D, Andrisani O Gut
Combination therapy for advanced hepatocellular carcinoma: do we see the light at the end of the tunnelZhang T, Merle P, Wang H, Zhao H, Kudo M HepatoBiliary Surgery and Nutrition
Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpressionDecaens T, Barone C, Assenat E, Wermke M, Fasolo A, Merle P, Blanc JF, Grando V, Iacobellis A, Villa E, Trojan J, Straub J, Bruns R, Berghoff K, Scheele J, Raymond E, Faivre S British Journal of Cancer
Health-related quality-of-life impact of pembrolizumab versus best supportive care in previously systemically treated patients with advanced hepatocellular carcinoma: KEYNOTE-240Ryoo BY, Merle P, Kulkarni AS, Cheng AL, Bouattour M, Lim HY, Breder V, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Daniele B, Norquist JM, Chen E, Siegel AB, Zhu AX, Finn RS, Kudo M Cancer
External validation of the French alpha-fetoprotein model for hepatocellular carcinoma liver transplantation in a recent unicentric cohort – a retrospective studyMourad M, Lebossé F, Merle P, Levrero M, Antonini T, Lesurtel M, Ducerf C, Zoulim F, Mabrut JY, Mohkam K Transplant International
Dissecting the Molecular Determinants of GABA A Receptors Current Rundown, a Hallmark of Refractory Human EpilepsyCifelli P, Di Angelantonio S, Alfano V, Morano A, De Felice E, Aronica E, Ruffolo G, Palma E Brain Science
Downregulation of miR-326 and its host gene β-arrestin1 induces pro-survival activity of E2F1 and promotes medulloblastoma growthMiele E, Po A, Mastronuzzi A, Carai A, Besharat ZM, Pediconi N, Abballe L, Catanzaro G, Sabato C, De Smaele E, Canettieri G, Di Marcotullio L, Vacca A, Mai A, Levrero M, Pfister SM, Kool M, Giangaspero F, Locatelli F, Ferretti E Molecular Oncology
Preliminary Evidence for Hepatitis Delta Virus Exposure in Patients Who Are Apparently Not Infected With Hepatitis B VirusChemin I, Pujol FH, Scholtès C, Loureiro CL, Amirache F, Levrero M, Zoulim F, Pérez-Vargas J, Cosset FL Hepatology
Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinomaJühling F, Hamdane N, Crouchet E, Li S, El Saghire H, Mukherji A, Fujiwara N, Oudot MA, Thumann C, Saviano A, Roca Suarez AA, Goto K, Masia R, Sojoodi M, Arora G, Aikata H, Ono A, Tabrizian P, Schwartz M, Polyak SJ, Davidson I, Schmidl C, Bock C, Schuster C, Chayama K, Pessaux P, Tanabe KK, Hoshida Y, Zeisel MB, Duong FH, Fuchs BC, Baumert TF Gut
The New Immuno-Oncology-Based Therapies and Their Perspectives in Hepatocellular CarcinomaMerle P Cancers
Hepatitis B virus-associated hepatocellular carcinoma is still a matter of concern in the French Caribbean Island of GuadeloupeBenard J, Lafrance MJ, Gordien E, Amaral L, Levrero M, Zoulim F, Saillard E, Gelu-Simeon M Clin Res Hepatol Gastroenterol
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Essential Oils as Alternative Biocides for the Preservation of Waterlogged Archaeological Wood
Antonelli F, Bartolini M, Plissonnier ML, Esposito A, Galotta G, Ricci S, Davidde Petriaggi B, Pedone C, Di Giovanni A, Piazza S, Guerrieri F*, Romagnoli M* Microorganisms
Use of next-generation sequencing to evaluate the risk of biodegradationAntonelli, F., Esposito, A., Galotta, G., ...Romagnoli, M., Guerrieri, F Applied Sciences (Switzerland)
Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongationConi S, Serrao SM, Yurtsever ZN, Di Magno L, Bordone R, Bertani C, Licursi V, Ianniello Z, Infante P, Moretti M, Petroni M, Guerrieri F, Fatica A, Macone A, De Smaele E, Di Marcotullio L, Giannini G, Maroder M, Agostinelli E, Canettieri G Cell Death & Disease
p53 functional loss, stemness and hepatocellular carcinomaCaron de Fromentel C, Levrero M Hepatoma Research
DLEU2 lncRNA and sustains viral and host transcriptionSalerno D, Chiodo L, Cottone G, Pallocca M, Jeddari S, Levrero M, Guerrieri F Gut
. Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2Kudo M, Galle PR, Brandi G, Kang YK, Yen CJ, Finn RS, Llovet JM, Assenat E, Merle P, ....., Widau RC, Zhu AX JHEP Reports
PARP inhibitors and radiation potentiate liver cell death in vitro. Do hepatocellular carcinomas have an achilles’ heel?Gerossier L, Dubois A, Paturel A, Fares N, Cohen D, Merle P, …, Bieche I, Hernandez-Vargas H, Hall J, Chemin I Clin Res Hepatol Gastroenterol
Management of immune checkpoint inhibitors-induced liver toxicity in cancerLebossé F, Bancel B, Levrero M, Merle P Bulletin du Cancer
Serum Alpha-fetoprotein Levels and Clinical Outcomes in the Phase III CELESTIAL Study of Cabozantinib versus Placebo in Patients with Advanced Hepatocellular CarcinomaKelley RK, Meyer T, Rimassa L, Merle P, Park JW, Yau T, Chan SL, Blanc JF, Tam VC, Tran A, Dadduzio V, Markby DW, Kaldate R, Cheng AL, El-Khoueiry AB, Abou-Alfa GK Clinical Cancer Research
Restoration of RNA helicase DDX5 suppresses hepatitis B virus (HBV) biosynthesis and Wnt signaling in HBV-related hepatocellular carcinomaMani SKK, Yan B, Cui Z, Sun J, Utturkar S, Foca A, Fares N, Durantel D, Lanman N, Merle P, Kazemian M, Andrisani O Theranostics
Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2Kudo M, Galle PR, Llovet JM, Finn RS, Vogel A, Motomura K, Assenat E, Merle P, Brandi G, ...., Yoshikawa R, Zhu AX Liver International
Structural Variations of Vaginal and Endometrial Microbiota: Hints on Female InfertilityRiganelli L, Iebba V, Piccioni M, Illuminati I, ..., Levrero M, Merlino L, ..., Schippa S, Guerrieri F Front Cell Infect Microbiol
Proteomics analysis of FUS mutant human motoneurons reveals altered regulation of cytoskeleton and other ALS-linked proteins via 3’UTR bindingGarone MG*, Alfano V*, Salvatori B, Braccia C, Peruzzi G, Colantoni A, Bozzoni I, Armirotti A, Rosa A Scientific Reports
Chlamydia trachomatis elicits TLR3 expression but disrupts the inflammatory signaling down-modulating NFκB and IRF3 transcription factors in human Sertoli cellsDi Pietro M, Filardo S, Alfano V, Pelloni M, Splendiani E, Po A, Paoli D, Ferretti E, Sessa R J Biol Regul Homeost Agents
Nasal Microbiota in RSV BronchiolitisSchippa S, Frassanito A, Marazzato M, Nenna R, Petrarca L, Neroni B, Bonfiglio G, Guerrieri F, Frasca F, Oliveto G, Pierangeli A, Midulla F Microorganisms
Atezolizumab plus Bevacizumab in Unresectable Hepatocellular CarcinomaFinn RS, Qin S, Ikeda M, ..., Merle P, Kaseb AO, ..., Zhu AX, Cheng AL; IMbrave150 Investigators New Engl J Med
Electrophysiological features of chronic inflammatory demyelinating polyradiculoneuropathy associated with IgG4 antibodies targeting neurofascin 155 or contactin 1 glycoproteinsKouton L, Boucraut J, Devaux J, ...., Merle P, ...., Attarian S, Delmont E Clinical Neurophysiology
Hepatitis C Virus Entry: An Intriguingly Complex and Highly Regulated ProcessColpitts CC, Tsai PL, Zeisel MB Int J Mol Sci
A Hyper-Glycosylation of HBV Surface Antigen Correlates with HBsAg-Negativity at Immunosuppression-Driven HBV Reactivation in Vivo and Hinders HBsAg Recognition in VitroSalpini R, Piermatteo L, Battisti A, ...., Levrero M, Perno CF, Belloni L, Svicher V Viruses
A functional microRNA screen uncovers O-linked N-acetylglucosamine transferase as a host factor modulating hepatitis C virus morphogenesis and infectivityHerzog K, Bandiera S,..., Zeisel MB. GUT
A combined small molecule and loss-of-function screen uncovers estrogen 2 receptor alpha and CAD as host factors for HDV infection and antiviral targetsVerrier ER,…, Zeisel MB,…, Baumert Gut
Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infectionBarili V, Fisicaro P, Montanini B, ...., Guerrieri F, ...., Levrero M, Ottonello S, Ferrari C Nature Communications
Characterization of black patina from the Tiber River embankments using Next-Generation SequencingAntonelli A, Esposito A, Calvo L, Licursi V, Tysseire P, Ricci S, Romagnoli M, Piazza S, Guerrieri F PLoS One
Hepatitis Delta Virus histone mimicry drives the recruitment of chromatin remodelers for viral RNA replicationAbeywickrama-Samarakoon N, Cortay JC, Sureau C, Müller S, Alfaiate D, Guerrieri F, Chaikuad A, Schröder M, Merle P, Levrero M, Dény P Nature Communications
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Inducing and Characterizing Vesicular Steatosis in Differentiated HepaRG Cells
Di Cocco S, Belloni L, Nunn ADG, Salerno D, Piconese S, Levrero M, Pediconi N. J Vis Exp
EZH2, JMJD3, and UTX epigenetically regulate hepatic plasticity inducing retro-differentiation and proliferation of liver cellsPediconi N, Salerno D, Lupacchini L, Angrisani A, Peruzzi G, De Smaele E, Levrero M, Belloni L Cell Death Dis
Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients.Testoni B, Lebossé F, Scholtes C, Berby F, Miaglia C, Subic M, Loglio A, Facchetti F, Lampertico P, Levrero M, Zoulim F J Hepatol
HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic responseHamdane N, Jühling F,…, Zeisel MB,…, Baumert TF Gastroenterology.
Microglia-Derived Microvesicles Affect Microglia Phenotype in GliomaGrimaldi A, Serpe C, Chece G, Nigro V, Sarra A, Ruzicka B, Relucenti M, Familiari G, Ruocco G, Pascucci GR, Guerrieri F, Limatola C, Catalano M. Front Cell Neurosci
Effect of food preservatives and additives in promoting intestinal inflammationLaudisi F, Di Fusco D, Dinallo V, Stolfi C, Di Grazia A, Marafini I, Colantoni A, Ortenzi A, Alteri C, Guerrieri F, Ceccherini-Silberstein F, Federici M, Monteleone I, and Monteleone G Cell Mol Gastroenterol Hepatol
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The novel HBx mutation F30V correlates with hepatocellular carcinoma in vivo, reduces hepatitis B virus replicative efficiency and enhances anti-apoptotic activity of HBx N terminus in vitro
Salpini R,…, Levrero M,…, Svicher V Clin Microbiol Infect .
Targeting a phospho-STAT3-miRNAs pathway improves vesicular hepatic steatosis in an in vitro and in vivo modelBelloni L,…, Guerrieri F,…, Levrero M, Pediconi N Sci Rep
Combining amplicon sequencing and metabolomics in cirrhotic patients highlights distinctive microbiota features involved in bacterial translocation, systemic inflammation and hepatic encephalopathyIebba V, Guerrieri F, Di Gregorio V, Levrero M, Gagliardi A, Santangelo F, Sobolev AP, Circi S, Giannelli V, Mannina L, Schippa S, Merli M Sci Rep
miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesisVan Renne N,…, Zeisel MB,…, Lupberger J. GUT
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Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus
Plissonnier ML, Lahlali T, Raab M, Michelet M, Romero-López C, Rivoire M, Strebhardt K, Durantel D, Levrero M, Mehlen P, Zoulim F, Parent R Oncogene
Cell death and restoration of TRAIL-sensitivity by ciglitazone in resistant cervical cancer cellsPlissonnier ML, Fauconnet S, Bittard H, Mougin C, Rommelaere J, Lascombe I ONcotarget
PRMT5 Restricts Hepatitis B Virus Replication via Epigenetic Repression of cccDNA Transcription and Interference with pgRNA EncapsidationZhang W, Chen J, Wu M, Zhang X, Zhang M, Yue L, Li Y, Liu J, Li B, Shen F, Wang Y, Bai L, Protzer U, Levrero M, Yuan Z Hepatology
Genome-wide identification of direct HBx genomic targetsGuerrieri F, Belloni L, D'Andrea D, Pediconi N, Le Pera L, Testoni B, Scisciani C, Floriot O, Zoulim F, Tramontano A, Levrero M BMC Genomics
Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis BFisicaro P, Barili V, Montanini B, Acerbi G, Ferracin M, Guerrieri F, Salerno D, Boni C, Massari M, Cavallo MC, Grossi G, Giuberti T, Lampertico P, Missale G, Levrero M, Ottonello S, Ferrari C Nat Med