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Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22237-42. doi: 10.1073/pnas.1015793108. Epub 2010 Dec 6.

Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis.

Author information

  • 1Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.

Abstract

Etiologic risk factors for hepatocellular carcinoma can be involved in the transformation process by directly targeting intracellular signaling pathways or by indirectly stimulating chronic cycles of hepatocyte destruction and regeneration. However, the contribution of these two routes to hepatocarcinogenesis has not been determined, partly because of the difficulty in distinguishing damaged and regenerated hepatocytes. Here we report that induced deletion of the damaged DNA binding protein 1 (DDB1) abrogates the self-renewing capacity of hepatocytes, resulting in compensatory proliferation of DDB1-expressing hepatocytes. Constitutive stimulation of this regeneration process leads to development of hepatocellular carcinoma, which surprisingly contains no disruption of the DDB1 gene, indicating a cell-nonautonomous role of DDB1 inactivation in tumor initiation. Our results suggest that viruses and hepatoxins may cause liver tumors by simply driving hepatocyte turnover without directly targeting cancer cells.

PMID:
21135245
[PubMed - indexed for MEDLINE]
PMCID:
PMC3009836
Free PMC Article

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