title: Arsenic trioxide attenuates the invasion potential of human liver cancer cells through the demethylation-activated microRNA-491.
abstract: 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 κB (NF-κB), 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.
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Mu
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Xianqing
authors.initials: X
authors.lastname: Ye
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Si
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Shilong
authors.initials: S
authors.lastname: Ning
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China. Electronic address: lz_ny@njmu.edu.cn.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, PR China. Electronic address: liyuannjmu@hotmail.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010087:Oxides / Q000633:toxicity*; D015398:Signal Transduction
chemical_list: D001152:Arsenicals; D015415:Biomarkers; C551410:MIRN491 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D010087:Oxides; D000077237:Arsenic Trioxide
keywords: Arsenic trioxide; Epithelial-mesenchymal transition; Hepatocellular carcinoma; Matrix metalloproteinases; MicroRNA-491; Nuclear factor κB