title: Induction of the mesenchymal to epithelial transition by demethylation- activated microRNA-200c is involved in the anti-migration/invasion effects of arsenic trioxide on human breast cancer cells.
abstract: Breast cancer is a major health problem worldwide. Current standard practices for treatment of breast cancer are less than satisfactory because of high rates of metastasis. Arsenic trioxide (As(2)O(3)), which induces demethylation of DNA and causes apoptosis, has been used as an anti-tumor agent. Little is known, however, regarding its anti-metastatic effects. The microRNA-200c (miR-200c), which is frequently lowly expressed in triple negative breast cancers (TNBCs), inhibits metastasis by inducing the mesenchymal to epithelial transition (MET). Here, we report that As(2)O(3) attenuates the migratory and invasive capacities of breast cancer cells, MDA-MB-231 and BT-549. Notably, As(2)O(3) induces an MET in vitro and in vivo, as determined by the increased expression of the epithelial marker, E-cadherin and decreased expressions of mesenchymal markers, N-cadherin and vimentin. Moreover, As(2)O(3) up-regulates the expression of miR-200c through demethylation. Over-expression of miR-200c enhances the expression of E-cadherin and decreases the expressions of N-cadherin and vimentin. Further, in MDA-MB-231 cells exposed to As(2)O(3), knockdown of miR-200c blocks the As(2)O(3) -induced MET. Finally, in MDA-MB-231 and BT-549 cells exposed to As(2)O(3), knockdown of miR-200c decreases the As(2)O(3) -induced inhibition of the migratory and invasive capacities. By identifying a mechanism whereby As(2)O(3) regulates miR-200c and MET, the results establish the anti-migration/invasion potential of arsenic trioxide.
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition, Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Si
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition, Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition, Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition, Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Xianqing
authors.initials: X
authors.lastname: Ye
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition, Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Mu
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition, Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition, Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Shilong
authors.initials: S
authors.lastname: Ning
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition, Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: Key Laboratory of Modern Toxicology, Ministry of Education, Department of Nutrition, Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D010087:Oxides / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D010087:Oxides; D000077237:Arsenic Trioxide
keywords: arsenic trioxide; breast cancer; mesenchymal to epithelial transition; microRNA-200c; migration/invasion