title: Thyroid hormone regulation of miR-21 enhances migration and invasion of hepatoma.
abstract: Thyroid hormone (T(3)) 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 T(3) through a native T(3) response element in the primary miR-21 promoter. Overexpression of miR-21 promoted hepatoma cell migration and invasion, similar to that observed with T(3) stimulation in hepatoma cells. In addition, anti-miR-21-induced suppression of cell migration was rescued by T(3). 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 T(3). 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 TRα1, 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 TRα1 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 T(3) and subsequent TIAM1 suppression promotes hepatoma cell migration and invasion.
authors: Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors: Ya-Hui
authors: YH
authors: Huang
authors: Yang-Hsiang
authors: YH
authors: Lin
authors: Hsiang-Cheng
authors: HC
authors: Chi
authors: Chen-Hsin
authors: CH
authors: Liao
authors: Chia-Jung
authors: CJ
authors: Liao
authors: Sheng-Ming
authors: SM
authors: Wu
authors: Cheng-Yi
authors: CY
authors: Chen
authors: Yi-Hsin
authors: YH
authors: Tseng
authors: Chung-Ying
authors: CY
authors: Tsai
authors: Sheng-Yen
authors: SY
authors: Lin
authors: Yu-Ting
authors: YT
authors: Hung
authors: Chih-Jen
authors: CJ
authors: Wang
authors: Crystal D
authors: CD
authors: Lin
authors: Kwang-Huei
authors: KH
authors: Lin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D023061:Gene Order; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D020218:Response Elements; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D013963:Thyroid Hormones / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D011988:Receptors, Thyroid Hormone; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D013963:Thyroid Hormones; D014284:Triiodothyronine