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CCAAT/Enhancer Binding Protein Knock-in Mice Exhibit Early Liver Glycogen Storage and Reduced Susceptibility to Hepatocellular Carcinoma

Departments of ¹ Physiology and ² Pathology, National University of Singapore and ³ Institute of Molecular and Cell Biology, Singapore, Singapore

Requests for reprints: Nai-dy Wang, Department of Physiology, National University of Singapore, Block MD9, 2 Medical Drive, Singapore 117597, Singapore. Phone: 65-6874-3663; Fax: 65-6778-8161; E-mail: phswnd{at}nus.edu.sg.

The CCAAT/enhancer binding protein (C/EBP) 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/EBP. Recent work showed reductions of C/EBP levels in human hepatocellular carcinoma with the reductions correlating to tumor size and progression. We investigated the potential of reactivating c/ebp expression during hepatic carcinogenesis to prevent tumor cell growth. We have developed a c/ebp knock-in mouse in which a single-copy c/ebp is regulated by one allele of the -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/ebp 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/EBP content in WT nodules whereas knock-in nodules stained strongly for C/EBP. The p21 protein was examined because it mediates a C/EBP 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/EBP-positive nodules were positive for nuclear p21, suggesting that C/EBP may be required to direct p21 to the cell nucleus to inhibit growth. Our data establish that controlled C/EBP production can inhibit liver tumor growth in vivo.

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