4.5 Article

Arsenic trioxide attenuates the invasion potential of human liver cancer cells through the demethylation-activated microRNA-491

期刊

TOXICOLOGY LETTERS
卷 227, 期 2, 页码 75-83

出版社

ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2014.03.016

关键词

Hepatocellular carcinoma; Arsenic trioxide; Matrix metalloproteinases; Epithelial-mesenchymal transition; MicroRNA-491; Nuclear factor kappa B

资金

  1. National Natural Science Foundation of China [81171987, 30972507]
  2. Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)

向作者/读者索取更多资源

Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related mortality worldwide. Current standard practices for treatment of HCC are less than satisfactory because of metastasis and recurrence. In addition to treating acute promyelocytic leukemia (APL), arsenic trioxide (As2O3) also suppresses other solid tumors, such as HCC. However, the effects of As2O3 on the migration/invasion potential of liver cancer cells and the molecular mechanisms underlying in remain unclear. Here we found that As2O3 attenuated the migration/invasion potential of HCC cell lines by blocking matrix metalloproteinases (MMPs) activities and inducing a mesenchymal to epithelial transition (MET). Indeed, As2O3 elevated the expression of microRNA-491 (miR-491) via demethylation. On one hand, as a target miRNA of MMP9, miR-491 decreased the MMP9 expression. On the other hand, miR-491 blocked the activation of nuclear factor kappa B (NF-kappa B), which transcriptionally inactivated MMP2 and induced a MET (as determined by the increased expression of E-cadherin and decreased expressions of snail, slug, and vimentin). Knockdown of miR-491 abolished the As2O3-induced MMPs inactivation, MET, and the migration/invasion potential of HCC cell lines. By understanding a novel mechanism how As2O3 inhibits the migration/invasion potential of liver cancer cells, our study may help to identify potential therapeutic targets for liver cancer. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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