title: Inhibition of TGF-β/SMAD3/NF-κB signaling by microRNA-491 is involved in arsenic trioxide-induced anti-angiogenesis in hepatocellular carcinoma cells.
abstract: Hepatocellular carcinoma (HCC) is 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, which are primarily attributed to the angiogenesis. So, the anti-angiogenesis treatment has become the new approach for HCC therapy. In addition to treating leukemia, arsenic trioxide (As2O3) also suppresses other solid tumors, including HCC. However, the roles of As2O3 in the angiogenesis potential of HCC cells remain unclear. In our present study, As2O3 attenuated the angiogenic ability by the microRNA-491 (miR-491)-mediated inhibition of TGF-β/SMAD3/NF-κB signal pathway in MHCC97H and MHCC97L cells. Briefly, in these cells, As2O3 improved the expression of miR-491 via DNA-demethylation; miR-491, which targeted the SMAD3-3'-UTR, decreased the expression/function of SMAD3, leading to the inactivation of NF-κB/IL-6/STAT-3 signaling; knockdown of miR-491 abolished the As2O3-induced inhibitions of the TGF-β/SMAD3/NF-κB pathway, the VEGF secretion, and the angiogenesis. By understanding a novel mechanism whereby As2O3 inhibits the angiogenic potential in HCC cells, our study would help in the design of future strategies of developing As2O3 as a potential chemopreventive agent when used alone or in combination with other current anticancer drugs.
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, 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, China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 210011, China.
authors.forename: Qinqiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of General Surgery, 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, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing 211166, China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: liyuannjmu@hotmail.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 210011, China. Electronic address: zjpnjmu@hotmail.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
mesh_terms: D020413:3' Untranslated Regions; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; 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*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D020533:Angiogenesis Inhibitors; D001152:Arsenicals; C551410:MIRN491 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D010087:Oxides; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077237:Arsenic Trioxide
keywords: Angiogenesis; Arsenic trioxide; Hepatocellular carcinoma; MicroRNA-491; Signal transduction