Abstract
RAP1, a component of the telomere-protective shelterin complex, has been shown to have both telomeric and non-telomeric roles. In the liver, RAP1 is involved in the regulation of metabolic transcriptional programs. RAP1-deficient mice develop obesity and hepatic steatosis, these phenotypes being more severe in females than in males. As hepatic steatosis and obesity have been related to increased liver cancer in mice and humans, we set out to address whether RAP1 deficiency resulted in increased liver cancer upon chemical liver carcinogenesis. We found that Rap1-/- females were more susceptible to DEN-induced liver damage and hepatocellular carcinoma (HCC). DEN-treated Rap1-/- female livers showed an earlier onset of both premalignant and malignant liver lesions, which were characterized by increased abundance of γH2AX-positive cells, increased proliferation and shorter telomeres. These findings highlight an important role for RAP1 in protection from liver damage and liver cancer.
Highlights
Primary liver cancer is the fifth and seventh most common cancer in men and women, respectively and the second leading cause of cancer-related death worldwide [1]
To address whether liver dysfunction associated to RAP1 deficiency synergizes with DEN-induced liver lesions in hepatocellular carcinoma (HCC) development, 2- week-old Rap1-/- and Rap1+/+ male and female mice were injected with DEN (25 mg /kg body weight)
We found that 40-weeks post-DEN treatment, the number of preneoplastic lesions including as follows. α-fetoprotein (AFP) & foci of altered hepatocytes (FAH) as well as hepatocellular adenomas (HCA) was significantly higher in RAP1-deficient females compared to treated wild-type females (Fig 3B and 3C)
Summary
Primary liver cancer is the fifth and seventh most common cancer in men and women, respectively and the second leading cause of cancer-related death worldwide [1]. Hepatocellular carcinoma (HCC) represents approximately 90% of all cases of primary liver cancer [1]. The incidence of liver cancer is increasingly on the rise and this is at least partly due to the growing epidemics of obesity and metabolic syndrome [3]. Mammalian telomeres are formed by TTAGGG repeats bound by a six-protein complex known as shelterin, which ensures telomere protection. Telomerase activity can compensate for telomere shortening by the addition of de novo TTAGGG repeats onto chromosome ends [18]. Telomerase is formed by a catalytic subunit known as TERT and an associated RNA component or Terc that is used as template for the addition of new telomeric repeats [18].
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