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.
Cavin
Lakita G
LG
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, College of Medicine, Memphis, Tennessee 38163, USA.
Venkatraman
Manickam
M
Factor
Valentina M
VM
Kaur
Swayamjot
S
Schroeder
Insa
I
Mercurio
Frank
F
Beg
Amer A
AA
Thorgeirsson
Snorri S
SS
Arsura
Marcello
M
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