ReviewTelomeres and telomerase: new targets for the treatment of liver cirrhosis and hepatocellular carcinoma
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):
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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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2023, Acta Pharmaceutica Sinica BCitation Excerpt :Most adult cells, including those in the liver, display low basal telomerase activity and low expression level of TERT due to telomeres shorten as a result of the incomplete replication of linear chromosomes. Emerging evidence suggests telomerase reactivation is involved in liver cirrhosis and hepatocellular carcinoma5,6. In metabolic liver diseases, telomerase enzyme deficiency promotes metabolic dysfunction in murine hepatocytes, and antioxidant treatment improves fatty liver via activating telomerase7,8.
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2011, European Journal of Pharmaceutics and BiopharmaceuticsCitation Excerpt :It was reported that high expression of hTERT could suppress apoptosis by multidifferentiation stimulation in some tumors [7]. More studies showed that inhibition of hTERT with the antisense or RNA interference (RNAi) technique could be a good antitumor strategy, which was successfully applied to reduce cancer cell growth [8,9]. Short hairpin RNA (shRNA) generated by a DNA vector, such as a plasmid, produces long-term, stable, and highly specific gene silencing.
The promoter of human telomerase reverse transcriptase is activated during liver regeneration and hepatocyte proliferation
2011, GastroenterologyCitation Excerpt :Indeed, telomerase activity can be induced in human lymphocytes.28 Thus, the activation of TERT in chronic hepatitis was thought to reflect an activation of telomerase in infiltrating lymphocytes.29 Experimental systems to investigate the activation of hTERT in regenerating hepatocytes have been missing.