DEPARTMENTS AND TEAMS / Immunity, Virus, Inflammation / 
Epigenetics and epigenomics of hepatocellular carcinoma (EpiHep)

CONTACT

Team Leader: Massimo Levrero
Bâtiment Inserm
151 Cours Albert Thomas
69424 Lyon Cedex 03

massimo.levrero@inserm.fr

04 72 68 19 79

04 72 68 19 70 (secretariat)
LEVRERO Massimo
University Professor - MD (UCLB - HCL)
massimo.levrero@inserm.fr
ZEISEL Mirjam
CR Inserm
mirjam.zeisel@inserm.fr
PLISSONNIER Marie-Laure
Research engineer Inserm
marie-laure.plissonnier@inserm.fr
GUERRIERI Francesca
Postdoctoral fellow
francesca.guerrieri@inserm.fr
ALFANO Vincenzo
Postdoctoral fellow
vincenzo.alfano@inserm.fr
PATUREL Alexia
Ph.D Student
alexia.paturel@inserm.fr
CHOUIK Yasmina
Ph.D Student
yasmina.chouik@inserm.fr
THIRION Margot
Ph.D Student
margot.thirion@inserm.fr
Voir les objectifs et projets Voir les publications

OBJECTIVES

Our team aim 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. 

PROJETS

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:

a) define the contribution of the viral protein HBx and HBc in HBV pathogenicity, liver tumors development and progression;

b) study the expression profiles of exhausted antigen specific CD8 lymphocytes in chronic HBV carriers and HBV-related HCCs and test new pharmacological correction strategies;

c) 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;

d) 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.

PUBLICATIONS

PRMT5 Restricts Hepatitis B Virus Replication via Epigenetic Repression of cccDNA Transcription and Interference with pgRNA Encapsidation. Zhang 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. 2017 Feb 25. doi: 10.1002/hep.29133.

Genome-wide identification of direct HBx genomic targets. Guerrieri 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. 2017 Feb 17;18(1):184. doi: 10.1186/s12864-017-3561-5.

Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Fisicaro 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. 2017 Feb 6. doi: 10.1038/nm.4275.

Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B patients. Lebossé F, Testoni B, Fresquet J, Facchetti F, Galmozzi E, Fournier M, Hervieu V, Berthillon P, Berby F, Bordes I, Durantel D, Levrero M, Lampertico P, Zoulim F. J Hepatol. 2016 Dec 30. pii: S0168-8278(16)30757-7. doi: 10.1016/j.jhep.2016.12.024.

HBV cure: why, how, when? Levrero M, Testoni B, Zoulim F. Curr Opin Virol. 2016 Jun;18:135-43. doi: 10.1016/j.coviro.2016.06.003. Review.

The histone deacetylase inhibiting drug Entinostat induces lipid accumulation in differentiated HepaRG cells. Nunn AD, Scopigno T, Pediconi N, Levrero M, Hagman H, Kiskis J, Enejder A. Sci Rep. 2016 Jun 20;6:28025. doi: 10.1038/srep28025.

Current treatments for chronic hepatitis B virus infections. Zoulim F, Lebossé F, Levrero M. Curr Opin Virol. 2016 Jun;18:109-16. doi: 10.1016/j.coviro.2016.06.004. Review.

Aiming for cure in HBV and HDV infection. Petersen J, Thompson AJ, Levrero M. J Hepatol. 2016 Oct;65(4):835-48. doi: 10.1016/j.jhep.2016.05.043. Review.

Mechanisms of HBV-induced hepatocellular carcinoma. Levrero M, Zucman-Rossi J. J Hepatol. 2016 Apr;64(1 Suppl):S84-101. doi: 10.1016/j.jhep.2016.02.021. Review.

IL6 Inhibits HBV Transcription by Targeting the Epigenetic Control of the Nuclear cccDNA Minichromosome. Palumbo GA, Scisciani C, Pediconi N, Lupacchini L, Alfalate D, Guerrieri F, Calvo L, Salerno D, Di Cocco S, Levrero M, Belloni L. PLoS One. 2015 Nov 18;10(11):e0142599. doi: 10.1371/journal.pone.0142599.

Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes. Testoni B, Durantel D, Lebossé F, Fresquet J, Helle F, Negro F, Donato MF, Levrero M, Zoulim F. Gut. 2016 Apr;65(4):672-82. doi: 10.1136/gutjnl-2014-309011.

Towards an HBV cure: state-of-the-art and unresolved questions--report of the ANRS workshop on HBV cure. Zeisel MB, Lucifora J, Mason WS, Sureau C, Beck J, Levrero M, Kann M, Knolle PA, Benkirane M, Durantel D, Michel ML, Autran B, Cosset FL, Strick-Marchand H, Trépo C, Kao JH, Carrat F, Lacombe K, Schinazi RF, Barré-Sinoussi F, Delfraissy JF, Zoulim F. Gut. 2015 Aug;64(8):1314-26. doi: 10.1136/gutjnl-2014-308943. Review.

TP63 and TP73 in cancer, an unresolved "family" puzzle of complexity, redundancy and hierarchy. Costanzo A, Pediconi N, Narcisi A, Guerrieri F, Belloni L, Fausti F, Botti E, Levrero M. FEBS Lett. 2014 Aug 19;588(16):2590-9. doi: 10.1016/j.febslet.2014.06.047.

HCV core-mediated activation of latent TGF-β via thrombospondin drives the crosstalk between hepatocytes and stromal environment. Benzoubir N, Lejamtel C, Battaglia S, Testoni B, Benassi B, Gondeau C, Perrin-Cocon L, Desterke C, Thiers V, Samuel D, Levrero M, Bréchot C, Bourgeade MF. J Hepatol. 2013 Dec;59(6):1160-8. doi: 10.1016/j.jhep.2013.07.036.

Position paper of the Italian Association for the Study of the Liver (AISF): the multidisciplinary clinical approach to hepatocellular carcinoma. Italian Association for the Study of the Liver (AISF).; AISF Expert Panel.; AISF Coordinating Committee., Bolondi L, Cillo U, Colombo M, Craxì A, Farinati F, Giannini EG, Golfieri R, Levrero M, Pinna AD, Piscaglia F, Raimondo G, Trevisani F, Bruno R, Caraceni P, Ciancio A, Coco B, Fraquelli M, Rendina M, Squadrito G, Toniutto P. Dig Liver Dis. 2013 Sep;45(9):712-23. doi: 10.1016/j.dld.2013.01.012.

Molecular mechanisms of HBV-associated hepatocarcinogenesis. Guerrieri F, Belloni L, Pediconi N, Levrero M. Semin Liver Dis. 2013 May;33(2):147-56. doi: 10.1055/s-0033-1345721. Review.

Mechanism of action of ribavirin in anti-HCV regimens: new insights for an age-old question? Testoni B, Levrero M, Durantel D. Gut. 2014 Jan;63(1):3-4. doi: 10.1136/gutjnl-2013-304528.
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