CircLRP6 Regulation of ZEB1 via miR-455 Is Involved in the Epithelial-Mesenchymal Transition During Arsenite-Induced Malignant Transformation of Human Keratinocytes. (1st December 2017)

• Record Type: Journal Article
• Authors: Xue, Junchao; Chen, Chao; Luo, Fei; Pan, Xueli; Xu, Hui; Yang, Ping; Sun, Qian; Liu, Xinlu; Lu, Lu; Yang, Qianlei; Xiao, Tian; Dai, Xiangyu; Luo, Peng; Lu, Jiachun; Zhang, Aihua; Liu, Qizhan
• Is Part Of: Toxicological sciences. Volume 162:Number 2(2018)
• Page Start: 450
• Page End: 461
• Publication Date: 2017-12-01
• Subjects: circRNAs -- miRNAs -- EMT -- carcinogenesis -- arsenite; Toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology; Periodicals; 615.9
• DOI: 10.1093/toxsci/kfx269
• Languages: English
• ISSNs: 1096-6080

Abstract

Abstract: 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.