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

摘要

MicroRNAs (miRNAs) are thought to control tumor metastasis through direct interactions with target genes. Thyroid hormone (T_(3)) and its receptor (TR) are involved in cell growth and cancer progression. However, the issue of whether miRNAs participate in T_(3)/TR-mediated tumor migration is yet to be established. In the current study, we demonstrated that T_(3)/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 鈭?234/鈭?000 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 T_(3), but partially reduced upon miR-17 overexpression. Notably, TR伪1 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 TR伪1 (P =0.033) and MMP3 (P =0.043) in HCC specimens. Data from our study suggest that T_(3)/TR, miR-17, p-AKT and MMP3 activities are interlinked in the regulation of cancer cell metastasis.