Format

Send to

Choose Destination
See comment in PubMed Commons below
Cancer Res. 2005 Nov 15;65(22):10330-7.

CCAAT/enhancer binding protein alpha knock-in mice exhibit early liver glycogen storage and reduced susceptibility to hepatocellular carcinoma.

Author information

  • 1Department of Physiology, National University of Singapore, Singapore.

Abstract

The CCAAT/enhancer binding protein alpha (C/EBPalpha) is vital for establishing normal hepatic energy homeostasis and moderating hepatocellular growth. CEBPA loss-of-function mutations identified in acute myeloid leukemia patients support a tumor suppressor role for C/EBPalpha. Recent work showed reductions of C/EBPalpha levels in human hepatocellular carcinoma with the reductions correlating to tumor size and progression. We investigated the potential of reactivating c/ebpalpha expression during hepatic carcinogenesis to prevent tumor cell growth. We have developed a c/ebpalpha knock-in mouse in which a single-copy c/ebpalpha is regulated by one allele of the alpha-fetoprotein (AFP) gene promoter. The knock-in mice are physically indistinguishable from wild-type (WT) controls. However, knock-in animals were found to deposit fetal hepatic glycogen earlier than WT animals. Quantitative real-time PCR confirmed early c/ebpalpha expression and early glycogen synthase gene activation in knock-in fetuses. We then used diethylnitrosamine to induce hepatocellular carcinoma in our animals. Diethylnitrosamine produced half the number of hepatocellular nodules in knock-in mice as in WT mice. Immunohistochemistry showed reduced C/EBPalpha content in WT nodules whereas knock-in nodules stained strongly for C/EBPalpha. The p21 protein was examined because it mediates a C/EBPalpha growth arrest pathway. Nuclear p21 was absent in WT nodules whereas cytoplasmic p21 was abundant; knock-in nodules were positive for nuclear p21. Interestingly, only C/EBPalpha-positive nodules were positive for nuclear p21, suggesting that C/EBPalpha may be required to direct p21 to the cell nucleus to inhibit growth. Our data establish that controlled C/EBPalpha production can inhibit liver tumor growth in vivo.

PMID:
16288022
DOI:
10.1158/0008-5472.CAN-04-4486
[PubMed - indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Support Center