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Cell Death Differ. 2015 Jun;22(6):1025-34. doi: 10.1038/cdd.2014.201. Epub 2014 Dec 19.

Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis.

Author information

1
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
2
1] Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA [2] Rancho Los Amigos Rehabilitation Center, Downey, CA, USA.
3
Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.

Abstract

The role of autophagy in carcinogenesis is controversial and apparently complex. By using mice with hepatocyte-specific knockout of Atg5, a gene essential for autophagy, we longitudinally studied the role of autophagy in hepatocarcinogenesis. We found that impairing autophagy in hepatocytes would induce oxidative stress and DNA damage, followed by the initiation of hepatocarcinogenesis, which could be suppressed by the antioxidant N-acetylcysteine. Interestingly, these mice developed only benign tumors with no hepatocellular carcinoma (HCC), even after the treatment with diethylnitrosamine, which induced HCC in wild-type mice. The inability of mice to develop HCC when autophagy was impaired was associated with the induction of multiple tumor suppressors including p53. Further analysis indicated that the induction of p53 was associated with the DNA-damage response. Tumorigenesis studies using an established liver tumor cell line confirmed a positive role of autophagy in tumorigenesis and a negative role of p53 in this process when autophagy was impaired. Our studies thus demonstrate that autophagy is required to maintain healthy mitochondria and to reduce oxidative stress and DNA damage to prevent the initiation of hepatocarcinogenesis. However, once hepatocarcinogenesis has been initiated, its presence is also required to suppress the expression of tumor suppressors to promote the development of HCC.

PMID:
25526090
PMCID:
PMC4423188
DOI:
10.1038/cdd.2014.201
[Indexed for MEDLINE]
Free PMC Article

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