期刊
TOXICOLOGICAL SCIENCES
卷 162, 期 2, 页码 450-461出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfx269
关键词
circRNAs; miRNAs; EMT; carcinogenesis; arsenite
类别
资金
- Natural Science Foundations of China [81430077]
- Postgraduate Innovation Project of Jiangsu province [CXZZ14_0421, CXZZ14_0951, KYLX15_0974]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
Circular RNAs (circRNAs), a class of noncoding RNAs generated from pre-mRNAs, participate in the regulation of tumorigenesis. The mechanism for regulation, however, is unclear. Here, to determine whether circRNAs are involved in arsenite-induced epithelial-mesenchymal transition (EMT) and malignant transformation in human keratinocyte (HaCaT) cells, the up-regulation of circLRP6 was confirmed in arsenite-transformed HaCaT (T-HaCaT) cells. In HaCaT cells, circLRP6 acted as an microRNA (miR)-455 sponge. For these cells, chronic exposure to arsenite caused an increase of circLRP6 and the transcription factor ZEB1, which induced the EMT. miR-455 suppressed the expression of ZEB1. Further, in T-HaCaT cells, knockdown of circLRP6 with siRNA inhibited ZEB1 expression, but cotransfection with circLRP6 siRNA and an miR-455 inhibitor reversed this inhibition. These results suggest that, in HaCaT cells, arsenite increases circLRP6 levels, which act as a sponge for miR-455 and up-regulate the miR-455 target, ZEB1, which subsequently induces the EMT, thus promoting malignant transformation. Thus, for HaCaT cells chronically exposed to arsenite, circLRP6 via miR-455 regulation of ZEB1 is involved in the EMT during malignant transformation. The results establish a previously unknown mechanism for arsenite-induced carcinogenesis.
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