Thyroid hormone regulation of mir-21 enhances migration and invasion of hepatoma

Ya Hui Huang, Yang Hsiang Lin, Hsiang Cheng Chi, Chen Hsin Liao, Chia Jung Liao, Sheng Ming Wu, Cheng Yi Chen, Yi Hsin Tseng, Chung Ying Tsai, Sheng Yen Lin, Yu Ting Hung, Chih Jen Wang, Crystal D. Lin, Kwang Huei Lin

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Abstract

Thyroid hormone (T3) signaling through the thyroid hormone receptor (TRα1) regulates hepatoma cell growth and pathophysiology, but the underlying mechanisms are unclear at present. Here, we have shown that the oncomir microRNA-21 (miR-21) is activated by T3 through a native T3 response element in the primary miR-21 promoter. Overexpression of miR-21 promoted hepatoma cell migration and invasion, similar to that observed with T3 stimulation in hepatoma cells. In addition, anti-miR-21-induced suppression of cell migration was rescued by T3. The Rac-controlled regulator of invasion and metastasis, T-cell lymphoma invasion and metastasis 1 (TIAM1), was identified as a miR-21 target additionally downregulated by T3. Attenuation and overexpression of miR-21 induced upregulation and downregulation of TIAM1, respectively. TIAM1 attenuation, in turn, enhanced migration and invasion via the upregulation of β-catenin, vimentin, and matrix metalloproteinase-2 in hepatoma cells. Notably, correlations between TRa1, miR-21, and TIAM1 expression patterns in animal models paralleled those observed in vitro. In the clinic, we observed a positive correlation (P=0.005) between the tumor/nontumor ratios of TRa1 and miR-21 expression, whereas a negative correlation (P = 0.019) was seen between miR-21 and TIAM1 expression in patients with hepatoma. Our findings collectively indicate that miR-21 stimulation by T3 and subsequent TIAM1 suppression promotes hepatoma cell migration and invasion. Cancer Res; 73(8); 2505-17.

Original languageEnglish
Pages (from-to)2505-2517
Number of pages13
JournalCancer Research
Volume73
Issue number8
DOIs
Publication statusPublished - 2013 Apr 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Huang, Y. H., Lin, Y. H., Chi, H. C., Liao, C. H., Liao, C. J., Wu, S. M., Chen, C. Y., Tseng, Y. H., Tsai, C. Y., Lin, S. Y., Hung, Y. T., Wang, C. J., Lin, C. D., & Lin, K. H. (2013). Thyroid hormone regulation of mir-21 enhances migration and invasion of hepatoma. Cancer Research, 73(8), 2505-2517. https://doi.org/10.1158/0008-5472.CAN-12-2218