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
Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
Department of Surgery, University of Virginia, Charlottesville, Virginia 22908-0625.
J Biol Chem. 2015 Jun 19;290(25):15549-15558. doi: 10.1074/jbc.M115.649707. Epub 2015 May 5.
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.
非甲状腺疾病综合征（NTIS）以血清3,5,3'-三碘甲状腺原氨酸（T3）水平降低而L-甲状腺素（T4）水平正常为特征，与恶性肿瘤相关。I型5'-脱碘酶（DIO1）活性降低，该酶可将T4转化为T3，是NTIS产生的原因之一。T3与甲状腺激素受体结合，后者与视黄酸X受体（RXR）形成异二聚体并调节靶基因（如DIO1）的转录。炎性细胞因子激活NF-κB会抑制DIO1表达。癌基因星形胶质细胞升高基因-1（AEG-1）会抑制RXR依赖性转录并激活NF-κB。在此，我们研究了AEG-1在肝细胞癌（HCC）背景下NTIS中的作用。在人肝癌细胞中，通过过表达或敲低AEG-1，以及来自AEG-1转基因（Alb/AEG-1）和AEG-1基因敲除（AEG-1KO）小鼠的原代肝细胞，分析了T3介导的基因调控。检测了Alb/AEG-1小鼠和人肝癌患者的血清T3和T4水平。通过免疫组织化学分析人肝癌样本中的AEG-1和DIO1水平。AEG-1抑制人肝癌细胞和小鼠肝细胞中T3介导的基因调控。AEG-1过表达会抑制，而AEG-1敲低会诱导DIO1表达。在人肝癌患者中观察到AEG-1和DIO1水平呈负相关。在肝癌患者和Alb/AEG-1小鼠的血清中观察到T4正常但T3降低。已确定抑制共激活因子募集到RXR和激活NF-κB在AEG-1介导的DIO1下调中起作用。因此，AEG-1可能在与HCC和其他癌症相关的NTIS中发挥作用。
