title: Caspase-2 deficiency accelerates chemically induced liver cancer in mice.
abstract: 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.
authors: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia.
authors: S
authors: S
authors: Shalini
authors: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia.
authors: A
authors: A
authors: Nikolic
authors: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia.
authors: C H
authors: CH
authors: Wilson
authors: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia.
authors: J
authors: J
authors: Puccini
authors: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia.
authors: N
authors: N
authors: Sladojevic
authors: SA Pathology and School of Medical and Veterinary Science, University of Adelaide, Adelaide, SA 5000, Australia.
authors: J
authors: J
authors: Finnie
authors: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia.
authors: L
authors: L
authors: Dorstyn
authors: Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia.
authors: S
authors: S
authors: Kumar
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D053143:Caspase 2 / Q000172:deficiency* / Q000378:metabolism; D016923:Cell Death; D049109:Cell Proliferation; D004249:DNA Damage; D004052:Diethylnitrosamine; D004789:Enzyme Activation; D007249:Inflammation / Q000150:complications / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D009367:Neoplasm Staging; D018384:Oxidative Stress; D013312:Stress, Physiological
chemical_list: D004052:Diethylnitrosamine; D048031:JNK Mitogen-Activated Protein Kinases; D053143:Caspase 2