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J Biol Chem. 2015 Jun 19;290(25):15549-58. doi: 10.1074/jbc.M115.649707. Epub 2015 May 5.

Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC).

Author information

1
From the Departments of Human and Molecular Genetics and.
2
the Department of Surgery, University of Virginia, Charlottesville, Virginia 22908-0625.
3
Biostatistics.
4
From the Departments of Human and Molecular Genetics and Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia 23298 and.
5
From the Departments of Human and Molecular Genetics and Massey Cancer Center, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia 23298 and dsarkar@vcu.edu.

Abstract

Non-thyroidal illness syndrome (NTIS), characterized by low serum 3,5,3'-triiodothyronine (T3) with normal l-thyroxine (T4) levels, is associated with malignancy. Decreased activity of type I 5'-deiodinase (DIO1), which converts T4 to T3, contributes to NTIS. T3 binds to thyroid hormone receptor, which heterodimerizes with retinoid X receptor (RXR) and regulates transcription of target genes, such as DIO1. NF-κB activation by inflammatory cytokines inhibits DIO1 expression. The oncogene astrocyte elevated gene-1 (AEG-1) inhibits RXR-dependent transcription and activates NF-κB. Here, we interrogated the role of AEG-1 in NTIS in the context of hepatocellular carcinoma (HCC). T3-mediated gene regulation was analyzed in human HCC cells, with overexpression or knockdown of AEG-1, and primary hepatocytes from AEG-1 transgenic (Alb/AEG-1) and AEG-1 knock-out (AEG-1KO) mice. Serum T3 and T4 levels were checked in Alb/AEG-1 mice and human HCC patients. AEG-1 and DIO1 levels in human HCC samples were analyzed by immunohistochemistry. AEG-1 inhibited T3-mediated gene regulation in human HCC cells and mouse hepatocytes. AEG-1 overexpression repressed and AEG-1 knockdown induced DIO1 expression. An inverse correlation was observed between AEG-1 and DIO1 levels in human HCC patients. Low T3 with normal T4 was observed in the sera of HCC patients and Alb/AEG-1 mice. Inhibition of co-activator recruitment to RXR and activation of NF-κB were identified to play a role in AEG-1-mediated down-regulation of DIO1. AEG-1 thus might play a role in NTIS associated with HCC and other cancers.

KEYWORDS:

AEG-1; NF-kappa B; hepatocellular carcinoma; liver; non-thyroidal illness syndrome; thyroid hormone; transcriptional coactivator

PMID:
25944909
PMCID:
PMC4505468
DOI:
10.1074/jbc.M115.649707
[Indexed for MEDLINE]
Free PMC Article

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