The acquisition of cancer stem cell-like properties and neoplastic transformation of human keratinocytes induced by arsenite involves epigenetic silencing of let-7c via Ras/NF-κB.
Exposure of humans to inorganic arsenic can cause skin cancer. The acquisition of cancer stem cell-like properties is involved in the initiation of some cancers, and there are changes in let-7 levels in some tumors. The mechanisms of action, however, remain obscure. Here, we report that there are decreased levels of let-7a, let-7b, and let-7c in human keratinocyte HaCaT cells during malignant transformation induced by a low concentration (1.0μM) of arsenite. The process by which arsenite reduces the level of let-7c apparently involves methylation, for 5-aza-2'-deoxycytidine, an inhibitor of methyltransferases, prevents arsenite-induced hypermethylation, decreases the level of let-7c, and thereby blocks arsenite-induced activation of the Ras/NF-κB signal pathway. Let-7c is an up-stream regulator of the Ras/NF-κB signal pathway and down-regulates activation of this pathway. In arsenite-transformed HaCaT cells, the acquisition of cancer stem cell-like properties is prevented by over-expression of let-7c, and over-expression of let-7c decreases the malignancy of transformed HaCaT cells. Thus, we conclude that epigenetic silencing of let-7c via Ras/NF-κB is involved in the acquisition of cancer stem cell-like properties and neoplastic transformation of HaCaT cells induced by arsenite, which contribute to the tumorigenesis of arsenite.
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
Rongrong
R
Jiang
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
Yuan
Y
Li
Department of Toxicology, School of Public Health, Guiyang Medical University, Guiyang 550004, Guizhou, PR China.
Aihua
A
Zhang
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
Bairu
B
Wang
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
Yuan
Y
Xu
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
Wenchao
W
Xu
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
Yue
Y
Zhao
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
Fei
F
Luo
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China. Electronic address: drqzliu@hotmail.com.
Qizhan
Q
Liu
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D001374:Azacitidine / Q000031:analogs & derivatives; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects; D017670:Sodium Compounds / Q000633:toxicity*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D018053:Arsenites; D035683:MicroRNAs; D016328:NF-kappa B; D017670:Sodium Compounds; C487931:mirnlet7 microRNA, human; C017947:sodium arsenite; D000077209:Decitabine; D018631:ras Proteins; D001374:Azacitidine
Arsenite; Cancer stem cell-like properties; Epigenetic regulation; Let-7c; Neoplastic transformation