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Thyroid hormone receptor represses miR-17 expression to enhance tumor metastasis in human hepatoma cells

Oncogene volume 32, pages 4509–4518 (2013)Cite this article

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Abstract

MicroRNAs (miRNAs) are thought to control tumor metastasis through direct interactions with target genes. Thyroid hormone (T3) and its receptor (TR) are involved in cell growth and cancer progression. However, the issue of whether miRNAs participate in T3/TR-mediated tumor migration is yet to be established. In the current study, we demonstrated that T3/TR negatively regulates mature miR-17 transcript expression, both in vitro and in vivo. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays localized the regions responding to TR-mediated repression to positions −2234/−2000 of the miR-17 promoter sequence. Overexpression of miR-17 markedly inhibited cell migration and invasion in vitro and in vivo, mediated via suppression of matrix metalloproteinases (MMP)-3. Moreover, p-AKT expression was increased in miR-17-knockdown cells that led to enhanced cell invasion, which was blocked by LY294002. Notably, low miR-17 expression was evident in highly metastatic cells. The cell migration ability was increased by T3, but partially reduced upon miR-17 overexpression. Notably, TRα1 was frequently upregulated in hepatocellular carcinoma (HCC) samples and associated with low overall survival (P=0.023). miR-17 expression was significantly negatively associated with TRα1 (P=0.033) and MMP3 (P=0.043) in HCC specimens. Data from our study suggest that T3/TR, miR-17, p-AKT and MMP3 activities are interlinked in the regulation of cancer cell metastasis.

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Acknowledgements

This work was supported by grants from Chang-Gung University, Taoyuan, Taiwan (CMRPD 34013, NMRP 140511) and from the National Science Council of the Republic of China (NSC 94-2320-B-182-052, NSC 98-2312-B-182A-001-MY3).

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Authors and Affiliations

  1. Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan, Republic of China

    Y-H Lin, C-J Liao, M-H Wu, H-C Chi, S-M Wu, C-Y Chen, Y-H Tseng, C-Y Tsai, I-H Chung, T-I Wu & K-H Lin

  2. Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan, Republic of China

    Y-H Huang

  3. Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan, Taiwan, Republic of China

    M-M Tsai

  4. Pre-med Program, Pacific Union College, Angwin, CA, USA

    C D Lin

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  1. Y-H Lin
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Lin, YH., Liao, CJ., Huang, YH. et al. Thyroid hormone receptor represses miR-17 expression to enhance tumor metastasis in human hepatoma cells. Oncogene 32, 4509–4518 (2013). https://doi.org/10.1038/onc.2013.309

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