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.
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Abbreviations
- HCC:
-
hepatocellular carcinoma
- DEN:
-
diethylnitrosamine
- ROS:
-
reactive oxygen species
- ALT:
-
alanine aminotransferase
- AST:
-
aspartate transaminase
- LDH:
-
lactate dehydrogenase
- ALP:
-
alkaline phosphatase
- TUNEL:
-
terminal deoxynucleotidyl transferase dUTP nick end labelling
- PCNA:
-
proliferating cell nuclear antigen
- HMGB1:
-
high-mobility group box 1
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Acknowledgements
We thank Alyshea Collaco for injecting mice and the staff at the SA Pathology animal resource facility for maintaining the mouse strains. This work was supported by the National Health and Medical Research Council (NHMRC) of Australia project grant (1021456), a Cancer Council Collaborative Research Fellowship to LD, an NHMRC Early Career Research Fellowship to CW (1073771) and NHMRC Senior Principal Research Fellowships (1002863 and 1103006) to SK.
Author contributions
SS, LD and SK conceptualised and designed the study; SS, AN, JP, CW and NS performed experiments; SS, AN, LD, CW and SK analysed the data; JF helped with tumour histopathology analyses; SS, CW and SK wrote and revised the paper. All authors commented on the manuscript drafts and edited the text.
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Shalini, S., Nikolic, A., Wilson, C. et al. Caspase-2 deficiency accelerates chemically induced liver cancer in mice. Cell Death Differ 23, 1727–1736 (2016). https://doi.org/10.1038/cdd.2016.81
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DOI: https://doi.org/10.1038/cdd.2016.81
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