Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aging sensitizes the liver to the hepatocarcinogenic effect of PPARalpha agonists via unknown mechanisms. This study was designed to investigate whether aging enhances the susceptibility of the liver to the anti-apoptotic effect of these chemicals. Since apoptosis serves to purge the liver of transformed cells, exaggerated inhibition of this process in aged livers may facilitate the progress of these cells to cancer. We quantified the effect of the PPARalpha agonists, clofibrate and Wy-14643, on the mRNA levels of various elements of the apoptotic machinery in male Fisher-344 rats ranging in age from immaturity (4-week-old), young adulthood (10-week-old), middle age (50-week-old), to senescence (100-week-old). Clofibrate and Wy-14643 either significantly diminished or exerted no effect on hepatic mRNA levels of several pro-apoptotic factors in immature, middle age and senescent animals. Unexpectedly, however, these PPARalpha agonists caused a remarkable 2- to 45-fold augmentation in the levels of the mRNA of Bax, caspase-2, and Fas mRNA in the young adult 10-week-old rats. A 47-75% decrease in the percent of apoptotic hepatocytes was observed only in 50- and 100-week-old rats treated with Wy-14643. Data suggest that activation of PPARalpha alters the balance between pro- and anti-apoptotic genes most significantly in livers of 50- and 100-week-old rats. Since suppression of apoptosis in the senescent liver is expected to diminish its ability to purge itself of already transformed cells, which may then progress to malignancy, exposure of senescent animals to PPARalpha agonists may be crucial to the ultimate outcome of liver cancer later in their life-span.
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PMID:Age-dependent effects of nongenotoxic hepatocarcinogens on liver apoptosis in vivo. 1266 31

Aberrant cell death/survival has a critical role in the development of hepatocellular carcinoma (HCC). Caspase-2, a cell death protease, limits oxidative stress and chromosomal instability. To study its role in reactive oxygen species (ROS) and DNA damage-induced liver cancer, we assessed diethylnitrosamine (DEN)-mediated tumour development in caspase-2-deficient (Casp2(-/-)) mice. Following DEN injection in young animals, tumour development was monitored for 10 months. We found that DEN-treated Casp2(-/-) mice have dramatically elevated tumour burden and accelerated tumour progression with increased incidence of HCC, accompanied by higher oxidative damage and inflammation. Furthermore, following acute DEN injection, liver injury, DNA damage, inflammatory cytokine release and hepatocyte proliferation were enhanced in mice lacking caspase-2. Our study demonstrates for the first time that caspase-2 limits the progression of tumourigenesis induced by an ROS producing and DNA damaging reagent. Our findings suggest that after initial DEN-induced DNA damage, caspase-2 may remove aberrant cells to limit liver damage and disease progression. We propose that Casp2(-/-) mice, which are more susceptible to genomic instability, are limited in their ability to respond to DNA damage and thus carry more damaged cells resulting in accelerated tumourigenesis.
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PMID:Caspase-2 deficiency accelerates chemically induced liver cancer in mice. 2751 36