title: Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC).
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.
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Srivastava
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Chadia L
authors.initials: CL
authors.lastname: Robertson
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gredler
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Siddiq
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Devaraja
authors.initials: D
authors.lastname: Rajasekaran
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Maaged A
authors.initials: MA
authors.lastname: Akiel
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia 22908-0625.
authors.forename: Valeria
authors.initials: V
authors.lastname: Mas
authors.affiliation: Biostatistics, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Nitai D
authors.initials: ND
authors.lastname: Mukhopadhyay
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298; Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298; VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298; Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298; VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia 23298. Electronic address: dsarkar@vcu.edu.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D005067:Euthyroid Sick Syndromes / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007453:Iodide Peroxidase / Q000096:biosynthesis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000235:genetics / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; C486321:Crisp1 protein, mouse; C483039:MTDH protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D047488:Retinoid X Receptors; D014284:Triiodothyronine; D007453:Iodide Peroxidase; C507436:selenodeiodinase type 1, mouse
keywords: AEG-1; NF-kappa B; hepatocellular carcinoma; liver; non-thyroidal illness syndrome; thyroid hormone; transcriptional coactivator