MicroRNA-21 activation of ERK signaling via PTEN is involved in arsenite-induced autophagy in human hepatic L-02 cells.
Autophagy, an evolutionarily conserved cellular process, has diverse physiological and pathological roles in biological functions. Whether autophagy is induced by arsenite, a well-established human carcinogen, and the molecular mechanisms involved, remain to be established. Further, microRNAs (miRNAs) act as regulators in various cancers, but how miRNAs regulate autophagy remains largely unexplored. We have found that, in human hepatic epithelial (L-02) cells, arsenite increases levels of autophagy-related proteins in a concentration- and time-dependent manner and elevates the number of autophagic vacuoles (AVs). Arsenite also activates the ERK pathway in a dose- and time-dependent manner. In L-02 cells exposed to arsenite, microRNA-21 (miRNA-21) is over-expressed, and its target proteins, PTEN, PDCD4, and Spry1, are decreased. Moreover, inhibition of miR-21 increases levels of PTEN, and reduces levels of Beclin 1 and LC3 II/I, indicating that miR-21 is involved in arsenite-induced autophagy. In addition, ectopic expression of PTEN blocks the effect of miR-21 on the arsenite-induced autophagy and decreases p-ERK levels. Also, ERK promotes the autophagy induced by arsenite. In sum, upon exposure of cells to arsenite, over-expression of miR-21 activates ERK through PTEN, factors that participate in arsenite-induced autophagy. This link, mediated through miRNAs, establishes a mechanism for the development of autophagy that is associated with arsenic toxicity. Such information contributes to an understanding of the liver toxicity caused by 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.
Xinlu
X
Liu
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
Jiangsu Center for Disease Control and Prevention, Nanjing 210009, Jiangsu, PR China.
Min
M
Ling
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.
Lu
L
Lu
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.
Le
L
Shi
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.
Xiaolin
X
Lu
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.
Hui
H
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.
Chao
C
Chen
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.
Qianlei
Q
Yang
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.
Junchao
J
Xue
The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang 550025, Guizhou, PR China.
Jun
J
Li
The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang 550025, 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. Electronic address: drqzliu@hotmail.com.
Qizhan
Q
Liu
D018053:Arsenites / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000633:toxicity*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
D018053:Arsenites; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D017670:Sodium Compounds; C017947:sodium arsenite; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
Arsenite; Autophagy; Extracellular regulated protein kinase (ERK); Gene of phosphate and tension homology deleted on chromosome ten (PTEN); miRNA-21