title: Thyroid hormone receptor represses miR-17 expression to enhance tumor metastasis in human hepatoma cells.
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.
authors.affiliation: Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan, Republic of China.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Lin
authors.forename: C-J
authors.initials: CJ
authors.lastname: Liao
authors.forename: Y-H
authors.initials: YH
authors.lastname: Huang
authors.forename: M-H
authors.initials: MH
authors.lastname: Wu
authors.forename: H-C
authors.initials: HC
authors.lastname: Chi
authors.forename: S-M
authors.initials: SM
authors.lastname: Wu
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chen
authors.forename: Y-H
authors.initials: YH
authors.lastname: Tseng
authors.forename: C-Y
authors.initials: CY
authors.lastname: Tsai
authors.forename: I-H
authors.initials: IH
authors.lastname: Chung
authors.forename: T-I
authors.initials: TI
authors.lastname: Wu
authors.forename: M-M
authors.initials: MM
authors.lastname: Tsai
authors.forename: C D
authors.initials: CD
authors.lastname: Lin
authors.forename: K-H
authors.initials: KH
authors.lastname: Lin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006980:Hyperthyroidism / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D020218:Response Elements; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism / Q000494:pharmacology
chemical_list: C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D051057:Proto-Oncogene Proteins c-akt; D019278:Matrix Metalloproteinase 3