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Regulation of -Fetoprotein by Nuclear Factor-B Protects Hepatocytes from Tumor Necrosis Factor- Cytotoxicity during Fetal Liver Development and Hepatic Oncogenesis

¹ Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, College of Medicine, Memphis, Tennessee; ² Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; ³ Celgene Signal Research Division, San Diego, California; and ⁴ Department of Biosciences, Columbia University, New York, New York

Nuclear factor-B (NF-B) plays a critical role during fetal liver development and hepatic oncogenesis. Here, we have assessed whether NF-B activity is required for murine hepatocellular carcinoma cell survival. We show that adenoviral-mediated inhibition of inhibitor of NF-B kinase-ß (IKK-2) activity in hepatocellular carcinomas derived from transforming growth factor (TGF)-/c-myc bitransgenic mice leads to inhibition of NF-B and promotes tumor necrosis factor (TNF)-–mediated cell death of malignant hepatocytes but not the surrounding peritumorous tissue. Induction of apoptosis is accompanied by inhibition of Bcl-X_L and XIAP, two pro-survival NF-B target genes. In addition, we have identified the -fetoprotein (AFP) as a novel downstream target of NF-B. We show that repression of IKK-2 activity in hepatocellular carcinomas promotes down-regulation of AFP gene expression. Likewise, genetic disruption of the RelA subunit results in reduced AFP gene expression during embryonic liver development, at a time in which fetal hepatocytes are sensitized to TNF-–mediated cell killing. In this regard, we show that AFP inhibits TNF-–induced cell death of murine hepatocellular carcinomas through association with TNF- and inhibition of TNFRI signaling. Thus, NF-B-mediated regulation of AFP gene expression during liver tumor formation and embryonic development of the liver constitutes a potential novel mechanism used by malignant and fetal hepatocytes to evade immune surveillance.

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