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Regulation of alpha-fetoprotein by nuclear factor-kappaB protects hepatocytes from tumor necrosis factor-alpha cytotoxicity during fetal liver development and hepatic oncogenesis.
- Source :
-
Cancer research [Cancer Res] 2004 Oct 01; Vol. 64 (19), pp. 7030-8. - Publication Year :
- 2004
-
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.
- Subjects :
- Adenoviridae genetics
Animals
Antigens, CD physiology
Apoptosis physiology
Gene Expression Regulation, Developmental
Hepatocytes metabolism
I-kappa B Kinase
Liver enzymology
Liver physiology
Liver Neoplasms, Experimental enzymology
Male
Mice
Mice, Transgenic
NF-kappa B genetics
NF-kappa B metabolism
Protein Serine-Threonine Kinases antagonists & inhibitors
Protein Serine-Threonine Kinases 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 physiology
X-Linked Inhibitor of Apoptosis Protein
alpha-Fetoproteins genetics
alpha-Fetoproteins metabolism
bcl-X Protein
Hepatocytes pathology
Liver embryology
Liver Neoplasms, Experimental pathology
NF-kappa B physiology
Tumor Necrosis Factor-alpha antagonists & inhibitors
alpha-Fetoproteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 64
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 15466196
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-04-1647