The role of telomeres and telomerase in cirrhosis and liver cancer

Abstract

Telomerase is a key enzyme for cell survival that prevents telomere shortening and the subsequent cellular senescence that is observed after many rounds of cell division. In contrast, inactivation of telomerase is observed in most cells of the adult liver. Absence of telomerase activity and shortening of telomeres has been implicated in hepatocyte senescence and the development of cirrhosis, a chronic liver disease that can lead to hepatocellular carcinoma (HCC) development. During hepatocarcinogenesis, telomerase reactivation is required to enable the uncontrolled cell proliferation that leads to malignant transformation and HCC development. Part of the telomerase complex, telomerase reverse transcriptase, is encoded by TERT, and several mechanisms of telomerase reactivation have been described in HCC that include somatic TERT promoter mutations, TERT amplification, TERT translocation and viral insertion into the TERT gene. An understanding of the role of telomeres and telomerase in HCC development is important to develop future targeted therapies and improve survival of this disease. In this Review, the roles of telomeres and telomerase in liver carcinogenesis are discussed, in addition to their potential translation to clinical practice as biomarkers and therapeutic targets.

Key points

  • Telomerase is a key enzyme for cell survival that prevents telomere shortening after cell divisions.

  • Cirrhosis is characterized by replicative senescence owing to short telomeres and no telomerase expression (TERT gene) in mature hepatocytes.

  • A return of telomerase expression is observed in 90% of hepatocellular carcinomas (HCC).

  • Mechanisms of telomerase reactivation in HCC are related to TERT promoter mutations, TERT amplification, chromosome translocations and HBV or adeno-associated virus type 2 viral insertion into the TERT promoter.

  • Several biomarkers and therapies directed against telomerase are in development, but none of them is currently validated for use in HCC.

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Fig. 1: Telomerase expression and telomere maintenance in the liver.
Fig. 2: Mechanisms of telomere maintenance in liver carcinogenesis.
Fig. 3: TERT promoter mutations across different histological types of cancer in human.
Fig. 4: Role of telomerase reactivation in the multistep process of liver carcinogenesis.
Fig. 5: Telomerase-based cancer therapies.

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Acknowledgements

This work was supported by Institut National du Cancer (INCa) with the International Cancer Genome Consortium (ICGC LICA-FR project) and NoFLIC projects (PAIR HCC, INCa and ARC), INSERM with the “Cancer et Environnement” (plan Cancer), MUTHEC projects (INCa), TELOTHEP project (PRTK2017 INCA) and HETCOLI projects (Tumor Heterogeneity and Ecosystem Program). The group is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmunology (investissement d’avenir), Coup d’Elan de la Fondation Bettencourt-Shueller, the SIRIC CARPEM, Fondation Mérieux, Prix Duquesne (Ligue Contre le Cancer, Comité de Paris) and Prix Raymond Rosen (Fondation pour la Recherche Médicale).

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All authors contributed equally to all aspects of the writing of this Review.

Correspondence to Jean-Charles Nault or Jessica Zucman-Rossi.

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