Elsevier

Journal of Hepatology

Volume 41, Issue 3, September 2004, Pages 491-497
Journal of Hepatology

Review
Telomeres and telomerase: new targets for the treatment of liver cirrhosis and hepatocellular carcinoma

https://doi.org/10.1016/j.jhep.2004.06.010Get rights and content

Introduction

Telomeres form the ends of eukoryotic chromosomes. The main function of telomeres is to stabilise chromosome ends thus to prevent chromosomal instability (CIS) and activation of DNA damage response. Telomere shortening due to the end replication problem of DNA polymerase limits the proliferative capacity of human cells to 50–70 cell doublings. The holoenzyme telomerase prevents ongoing telomere shortening by de novo synthesis of telomere repeats. However, in humans, postnatal telomerase expression is suppressed in most somatic tissues—including the liver. Telomere shortening limits the regenerative capacity of hepatocytes during chronic liver disease and hepatocellular senescence is associated with cirrhosis formation. In animal models, it has been shown that telomerase reactivation can improve liver regeneration and prevent cirrhosis formation induced by telomere shortening. The future use of telomerase activation for treatment of chronic liver disease depends on its effect on hepatocarcinogenesis. Telomerase reactivation appears to be required for hepatocellular carcinoma progression whereas telomere shortening is linked to CIS and tumor initiation. This review will focus on the role of telomere shortening and telomerase activation in cirrhosis and hepatocarcinogenesis and the potential use of telomerase activators or inhibitors for these disease stages.

Section snippets

Telomeres and telomerase

Telomeres are specialized protein-DNA structures at the end of linear eukaryotic chromosomes [1], [2], [3]. The main function of telomeres is to cap chromosomal ends in order to distinguish the chromosomal end from inappropriate DNA double strand breaks induced by DNA-damage. This telomere capping function is necessary to prevent chromosomal fusions and induction of DNA-damage responses (for review see Ref. [4]). Human telomeric DNA consists of conserved tandem repeats (TTAGGGn), which extends

Telomere shortening induces replicative senescence and chromosomal instability

The enzyme DNA-polymerase is unable to fully replicate the terminal portion of linear chromosomes during lagging strand DNA synthesis in the S-phase of the cell cycle [23]. Due to this end-replication problem telomeres shorten during each cell division by 50–100 base pairs [23]. When telomeres reach a critically short length telomeres loose their capping function at the chromosomal end [24]. Dysfunctional telomeres are sensed as DNA-damage and generate a DNA-damage signal [25], [26], [27]. The

Telomere shortening in cirrhosis and hepatocellular carcinoma

A variety of studies have demonstrated telomere shortening in chronic liver disease [46], [47], [48], [49], [50]. Most significant telomere shortening has been detected at the cirrhosis stage [46], [47], [48], [49], [50] and some of these studies have described a correlation between telomere shortening and cirrhosis progression [46], [47], [48], [50]. In addition, it has been shown that senescent cells accumulate in chronic liver disease [51] and at the cirrhosis stage [50]. Currently,

Telomerase activity in chronic liver disease, cirrhosis, and hepatocellular carcinoma

In normal human liver, there is no significant telomerase activity [56], [57], [58]. In contrast, some studies have reported a weak activation of telomerase during chronic viral hepatitis or cirrhosis [59], [60], [61]. However, it is not yet clear whether weak level of telomerase activity in hepatitis samples represent an activation of telomerase in hepatocytes. An alternative explanation could be that telomerase is activated in infiltrating lymphocytes in diseased liver. Activated human

The use of telomerase activators or inhibitors as therapeutic targets for liver cirrhosis and hepatocellular carcinoma

The above data suggest that in principle two therapeutic approaches for telomerase inhibition or activation could be used in liver disease (Fig. 2):

  • 1.

    Telomerase activation for prevention of hepatocellular senescence and improvement of hepatocyte regeneration at the cirrhosis stage.

Proof of principle for this approach has come from studies in mTERC−/− mice. In mTERC−/− mice telomerase activation by adenoviral mediated transfer of mTERC rescued telomerase activity in mouse liver. In this mouse

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References (99)

  • M.W. Djojosubroto et al.

    Telomeres and telomerase in aging, regeneration and cancer

    Mol Cells

    (2003)
  • K.L. Rudolph et al.

    Longevity, stress response, and cancer in aging telomerase-deficient mice

    Cell

    (1999)
  • I. Dokal

    Dyskeratosis congenita. A disease of premature ageing

    Lancet

    (2001)
  • A. Smogorzewska et al.

    DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2

    Curr Biol

    (2002)
  • R.A. Greenberg et al.

    Short dysfunctional telomeres impair tumorigenesis in the INK4a[delta2/3] cancer-prone mouse

    Cell

    (1999)
  • T. Kitada et al.

    Telomere shortening in chronic liver diseases

    Biochem Biophys Res Commun

    (1995)
  • N. Miura et al.

    Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis

    Cancer Genet Cytogenet

    (1997)
  • H. Aikata et al.

    Telomere reduction in human liver tissues with age and chronic inflammation

    Exp Cell Res

    (2000)
  • V. Paradis et al.

    Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas

    Hum Pathol

    (2001)
  • H. Kojima et al.

    Telomerase activity and telomere length in hepatocellular carcinoma and chronic liver disease

    Gastroenterology

    (1997)
  • B.K. Oh et al.

    Telomere shortening and telomerase reactivation in dysplastic nodules of human hepatocarcinogenesis

    J Hepatol

    (2003)
  • F. Komine et al.

    Telomerase activity of needle-biopsied liver samples: its usefulness for diagnosis and judgement of efficacy of treatment of small hepatocellular carcinoma

    J Hepatol

    (2000)
  • H. Kojima et al.

    Quantitative evaluation of telomerase activity in small liver tumors: analysis of ultrasonography-guided liver biopsy specimens

    J Hepatol

    (1999)
  • S. Takahashi et al.

    Expression of telomerase component genes in hepatocellular carcinomas

    Eur J Cancer

    (2000)
  • T. Kobayashi et al.

    Telomerase expression and p53 status in hepatocellular carcinoma

    Am J Gastroenterol

    (2002)
  • T. Kobayashi et al.

    Telomerase activity as a predictive marker for recurrence of hepatocellular carcinoma after hepatectomy

    Am J Surg

    (2001)
  • Y.C. Liu et al.

    Telomerase and c-myc expression in hepatocellular carcinomas

    Eur J Surg Oncol

    (2004)
  • H. Wege et al.

    Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential

    Gastroenterology

    (2003)
  • L.R. Kelland

    Telomerase: biology and phase I trials

    Lancet Oncol

    (2001)
  • Y.C. Liu et al.

    Telomerase and c-myc expression in hepatocellular carcinomas

    Eur J Surg Oncol

    (2004)
  • K. Masutomi et al.

    Telomerase maintains telomere structure in normal human cells

    Cell

    (2003)
  • E.H. Blackburn

    Structure and function of telomeres

    Nature

    (1991)
  • R.K. Moyzis et al.

    A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes

    Proc Natl Acad Sci USA

    (1988)
  • Y. Liu et al.

    Preferential maintenance of critically short telomeres in mammalian cells heterozygous for mTert

    Proc Natl Acad Sci USA

    (2002)
  • G.N. Parkinson et al.

    Crystal structure of parallel quadruplexes from human telomeric DNA

    Nature

    (2002)
  • J. Kanoh et al.

    Composition and conservation of the telomeric complex

    Cell Mol Life Sci

    (2003)
  • D. Broccoli et al.

    Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2

    Nat Genet

    (1997)
  • L. Chong et al.

    A human telomeric protein

    Science

    (1995)
  • P. Baumann et al.

    Pot1, the putative telomere end-binding protein in fission yeast and humans

    Science

    (2001)
  • C.W. Greider et al.

    A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis

    Nature

    (1989)
  • W.E. Wright et al.

    Telomerase activity in human germline and embryonic tissues and cells

    Dev Genet

    (1996)
  • K. Collins et al.

    Telomerase in the human organism

    Oncogene

    (2002)
  • C.P. Chiu et al.

    Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow

    Stem Cells

    (1996)
  • M.K. Maini et al.

    Virus-induced CD8+T cell clonal expansion is associated with telomerase up-regulation and telomere length preservation: a mechanism for rescue from replicative senescence

    J Immunol

    (1999)
  • U.M. Martens et al.

    Telomere maintenance in human B lymphocytes

    Br J Haematol

    (2002)
  • K.F. Norrback et al.

    Telomerase regulation and telomere dynamics in germinal centers

    Eur J Haematol

    (2001)
  • N.P. Weng et al.

    Telomere lengthening and telomerase activation during human B cell differentiation

    Proc Natl Acad Sci USA

    (1997)
  • J. Nakayama et al.

    Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas

    Nat Genet

    (1998)
  • O.A. Sedelnikova et al.

    Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks

    Nat Cell Biol

    (2004)
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