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

Abstract

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.