Astrocyte elevated gene-1 (AEG-1) contributes to non-thyroidal illness syndrome (NTIS) associated with hepatocellular carcinoma (HCC)

Jyoti Srivastava, Chadia L. Robertson, Rachel Gredler, Ayesha Siddiq, Devaraja Rajasekaran, Maaged A. Akiel, Luni Emdad, Valeria Mas, Nitai D. Mukhopadhyay, Paul B. Fisher, Devanand Sarkar

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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.

Original languageEnglish (US)
Pages (from-to)15549-15558
Number of pages10
JournalJournal of Biological Chemistry
Volume290
Issue number25
DOIs
StatePublished - Jun 19 2015

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Euthyroid Sick Syndromes
Astrocytes
Hepatocellular Carcinoma
Genes
Retinoid X Receptors
Transcription
Gene expression
Hepatocytes
Serum
Chemical activation
Gene Knockdown Techniques
Thyroid Hormone Receptors
Gene Knockout Techniques

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Srivastava, J., Robertson, C. L., Gredler, R., Siddiq, A., Rajasekaran, D., Akiel, M. A., ... Sarkar, D. (2015). Astrocyte elevated gene-1 (AEG-1) contributes to non-thyroidal illness syndrome (NTIS) associated with hepatocellular carcinoma (HCC). Journal of Biological Chemistry, 290(25), 15549-15558. https://doi.org/10.1074/jbc.M115.649707

Astrocyte elevated gene-1 (AEG-1) contributes to non-thyroidal illness syndrome (NTIS) associated with hepatocellular carcinoma (HCC). / Srivastava, Jyoti; Robertson, Chadia L.; Gredler, Rachel; Siddiq, Ayesha; Rajasekaran, Devaraja; Akiel, Maaged A.; Emdad, Luni; Mas, Valeria; Mukhopadhyay, Nitai D.; Fisher, Paul B.; Sarkar, Devanand.

In: Journal of Biological Chemistry, Vol. 290, No. 25, 19.06.2015, p. 15549-15558.

Research output: Contribution to journalArticle

Srivastava, J, Robertson, CL, Gredler, R, Siddiq, A, Rajasekaran, D, Akiel, MA, Emdad, L, Mas, V, Mukhopadhyay, ND, Fisher, PB & Sarkar, D 2015, 'Astrocyte elevated gene-1 (AEG-1) contributes to non-thyroidal illness syndrome (NTIS) associated with hepatocellular carcinoma (HCC)', Journal of Biological Chemistry, vol. 290, no. 25, pp. 15549-15558. https://doi.org/10.1074/jbc.M115.649707
Srivastava, Jyoti ; Robertson, Chadia L. ; Gredler, Rachel ; Siddiq, Ayesha ; Rajasekaran, Devaraja ; Akiel, Maaged A. ; Emdad, Luni ; Mas, Valeria ; Mukhopadhyay, Nitai D. ; Fisher, Paul B. ; Sarkar, Devanand. / Astrocyte elevated gene-1 (AEG-1) contributes to non-thyroidal illness syndrome (NTIS) associated with hepatocellular carcinoma (HCC). In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 25. pp. 15549-15558.
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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.",
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