Regulation of alpha-fetoprotein by nuclear factor-kappaB protects hepatocytes from tumor necrosis factor-alpha cytotoxicity during fetal liver development and hepatic oncogenesis.

Abstract

Nuclear factor-kappaB (NF-kappaB) plays a critical role during fetal liver development and hepatic oncogenesis. Here, we have assessed whether NF-kappaB activity is required for murine hepatocellular carcinoma cell survival. We show that adenoviral-mediated inhibition of inhibitor of NF-kappaB kinase-beta (IKK-2) activity in hepatocellular carcinomas derived from transforming growth factor (TGF)-alpha/c-myc bitransgenic mice leads to inhibition of NF-kappaB and promotes tumor necrosis factor (TNF)-alpha-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-kappaB target genes. In addition, we have identified the alpha-fetoprotein (AFP) as a novel downstream target of NF-kappaB. 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-alpha-mediated cell killing. In this regard, we show that AFP inhibits TNF-alpha-induced cell death of murine hepatocellular carcinomas through association with TNF-alpha and inhibition of TNFRI signaling. Thus, NF-kappaB-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.

• Authors: Lakita G Cavin, Manickam Venkatraman, Valentina M Factor, Swayamjot Kaur, Insa Schroeder, Frank Mercurio, Amer A Beg, Snorri S Thorgeirsson, Marcello Arsura
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 19 Pg. 7030-8 (Oct 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15466196 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, CD
• Bcl2l1 protein, mouse
• NF-kappa B
• Proteins
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc
• Receptors, Tumor Necrosis Factor
• Receptors, Tumor Necrosis Factor, Type I
• Transforming Growth Factor alpha
• Tumor Necrosis Factor-alpha
• X-Linked Inhibitor of Apoptosis Protein
• alpha-Fetoproteins
• bcl-X Protein
• Protein Serine-Threonine Kinases
• Chuk protein, mouse
• I-kappa B Kinase
• Ikbkb protein, mouse
• Ikbke protein, mouse

Topics

• Adenoviridae (genetics)
• Animals
• Antigens, CD (physiology)
• Apoptosis (physiology)
• Gene Expression Regulation, Developmental
• Hepatocytes (metabolism, pathology)
• I-kappa B Kinase
• Liver (embryology, enzymology, physiology)
• Liver Neoplasms, Experimental (enzymology, pathology)
• Male
• Mice
• Mice, Transgenic
• NF-kappa B (genetics, metabolism, physiology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proteins (antagonists & inhibitors)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Proto-Oncogene Proteins c-myc
• Receptors, Tumor Necrosis Factor (physiology)
• Receptors, Tumor Necrosis Factor, Type I
• Transforming Growth Factor alpha (antagonists & inhibitors)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, physiology)
• X-Linked Inhibitor of Apoptosis Protein
• alpha-Fetoproteins (genetics, metabolism, physiology)
• bcl-X Protein