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

Background: Astrocyte elevated gene-1 (AEG-1) inhibits retinoid X receptor (RXR) function and is overexpressed in human hepatocellular carcinoma (HCC), which is associated with non-thyroidal illness syndrome (NTIS). Results: AEG-1 inhibits thyroid hormone (T-3) function by down-regulating type I 5-deiodinase (DIO1) thus contributing to NTIS. Conclusion: A novel role of AEG-1 is identified regulating cancer-associated NTIS. Significance: AEG-1 inhibition might alleviate cancer-associated debilitating disorders. Non-thyroidal illness syndrome (NTIS), characterized by low serum 3,5,3-triiodothyronine (T-3) with normal l-thyroxine (T-4) levels, is associated with malignancy. Decreased activity of type I 5-deiodinase (DIO1), which converts T-4 to T-3, contributes to NTIS. T-3 binds to thyroid hormone receptor, which heterodimerizes with retinoid X receptor (RXR) and regulates transcription of target genes, such as DIO1. NF-B activation by inflammatory cytokines inhibits DIO1 expression. The oncogene astrocyte elevated gene-1 (AEG-1) inhibits RXR-dependent transcription and activates NF-B. Here, we interrogated the role of AEG-1 in NTIS in the context of hepatocellular carcinoma (HCC). T-3-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 T-3 and T-4 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 T-3-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 T-3 with normal T-4 was observed in the sera of HCC patients and Alb/AEG-1 mice. Inhibition of co-activator recruitment to RXR and activation of NF-B 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.