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

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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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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

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