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Supplementary Figure Legends from Regulation of α-Fetoprotein by Nuclear Factor-κB Protects Hepatocytes from Tumor Necrosis Factor-α Cytotoxicity during Fetal Liver Development and Hepatic Oncogenesis

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posted on 2023-03-30, 16:24 authored by Lakita G. Cavin, Manickam Venkatraman, Valentina M. Factor, Swayamjot Kaur, Insa Schroeder, Frank Mercurio, Amer A. Beg, Snorri S. Thorgeirsson, Marcello Arsura
Supplementary Figure Legends from Regulation of α-Fetoprotein by Nuclear Factor-κB Protects Hepatocytes from Tumor Necrosis Factor-α Cytotoxicity during Fetal Liver Development and Hepatic Oncogenesis

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ARTICLE ABSTRACT

Nuclear factor-κB (NF-κB) plays a critical role during fetal liver development and hepatic oncogenesis. Here, we have assessed whether NF-κB activity is required for murine hepatocellular carcinoma cell survival. We show that adenoviral-mediated inhibition of inhibitor of NF-κB kinase-β (IKK-2) activity in hepatocellular carcinomas derived from transforming growth factor (TGF)-α/c-myc bitransgenic mice leads to inhibition of NF-κB and promotes tumor necrosis factor (TNF)-α–mediated cell death of malignant hepatocytes but not the surrounding peritumorous tissue. Induction of apoptosis is accompanied by inhibition of Bcl-XL and XIAP, two pro-survival NF-κB target genes. In addition, we have identified the α-fetoprotein (AFP) as a novel downstream target of NF-κB. 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-α–mediated cell killing. In this regard, we show that AFP inhibits TNF-α–induced cell death of murine hepatocellular carcinomas through association with TNF-α and inhibition of TNFRI signaling. Thus, NF-κB-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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