title: Inhibition of the cancer stem cells-like properties by arsenic trioxide, involved in the attenuation of endogenous transforming growth factor beta signal.
abstract: The elevation of cancer stem cells (CSCs)-like properties is involved in the initiation and progression of various human cancers. Current standard practices for treatment of cancers are less than satisfactory because of CSCs-mediated recurrence. For this reason, targeting the CSCs or the cancer cells with CSCs-like properties has become the new approach for the cancer treatments. In addition to treating leukemia, arsenic trioxide (As₂O₃) also suppresses other solid tumors. However, the roles of As₂O₃ in the regulation of CSCs-like properties remain largely uninvestigated. Here by using sphere formation assay, luciferase reporter assay, and some other molecular biology approaches, we found that As₂O₃ attenuated the CSCs-like properties in human hepatocellular carcinoma (HCC). Briefly, in HCC cells and mice xenograft models, As₂O₃ improved the expression of miR-491 by DNA-demethylation. MiR-491, which targeted the SMAD3-3'-UTR, decreased the expressions of SMAD3, and inhibited the CSCs-like properties in HCC cells. Knockdown of either miR-491 or SMAD3 attenuated the As₂O₃-induced inhibition of endogenous transforming growth factor beta signal and the CSCs-like properties. Further, in HCC patients, miR-491 is inversely correlated with the expressions of SMAD3, CD133, and the metastasis/recurrence outcome. By understanding a novel mechanism whereby As₂O₃ inhibits the CSCs-like properties in HCC, our study would help in the design of future strategies of developing As₂O₃ as a potential HCC chemopreventive agent when used alone or in combination with other current drugs.
authors.affiliation: *The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Department of General Surgery and Department of Geriatrics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: *The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Department of General Surgery and Department of Geriatrics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jiang
authors.affiliation: *The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Department of General Surgery and Department of Geriatrics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, China.
authors.forename: Qinqiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: *The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Department of General Surgery and Department of Geriatrics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shen
authors.affiliation: *The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Department of General Surgery and Department of Geriatrics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Wang
authors.affiliation: *The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Department of General Surgery and Department of Geriatrics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: *The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Department of General Surgery and Department of Geriatrics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, China zjpnjmu@hotmail.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: *The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Department of General Surgery and Department of Geriatrics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 210011, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Lu
mesh_terms: D020413:3' Untranslated Regions; D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D001152:Arsenicals; D006023:Glycoproteins; C551410:MIRN491 microRNA, human; D035683:MicroRNAs; D010087:Oxides; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D000077237:Arsenic Trioxide
keywords: arsenic trioxide; cancer stem cells-like properties; hepatocellular carcinoma; microRNA-491; transforming growth factor beta