Regulation of alpha-fetoprotein by nuclear factor-kappaB protects hepatocytes from tumor necrosis factor-alpha cytotoxicity during fetal liver development and hepatic oncogenesis.
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.
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, College of Medicine, Memphis, Tennessee 38163, USA.
Lakita G
LG
Cavin
Manickam
M
Venkatraman
Valentina M
VM
Factor
Swayamjot
S
Kaur
Insa
I
Schroeder
Frank
F
Mercurio
Amer A
AA
Beg
Snorri S
SS
Thorgeirsson
Marcello
M
Arsura
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D051550:I-kappa B Kinase; D008099:Liver / Q000196:embryology* / Q000201:enzymology / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D016271:Proto-Oncogene Proteins c-myc; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051020:bcl-X Protein
D015703:Antigens, CD; C494812:Bcl2l1 protein, mouse; D016328:NF-kappa B; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; D000509:alpha-Fetoproteins; D051020:bcl-X Protein; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse