Circ008913,viamiR-889 regulation of DAB2IP/ZEB1, is involved in the arsenite-induced acquisition of CSC-like properties by human keratinocytes in carcinogenesis

Author(s): Tian Xiao ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Junchao Xue ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Ming Shi ⁶ ^, ² ^, ⁷ ^, ⁸ ^, ⁵ , Chao Chen ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Fei Luo ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Hui Xu ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Xiong Chen ⁹ ^, ¹⁰ ^, ² ^, ¹¹ ^, ¹² , Baofei Sun ⁹ ^, ¹⁰ ^, ² ^, ¹¹ ^, ¹² , Qian Sun ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Qianlei Yang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Xiangyu Dai ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Aihua Zhang ⁹ ^, ¹⁰ ^, ² ^, ¹¹ ^, ¹² , Huanwen Tang ⁶ ^, ² ^, ⁷ ^, ⁸ ^, ⁵ , Qizhan Liu ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵

Publication date (Electronic): 2018

Journal: Metallomics

Publisher: Royal Society of Chemistry (RSC)

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Abstract

Circ008913, viamiR-889 regulation of DAB2IP/ZEB1, is involved in the arsenite-induced acquisition of CSC-like properties and the neoplastic transformation.

Abstract

Arsenic is a known human carcinogen and the mechanisms underlying arsenic-induced tumorigenesis remain elusive. Circular RNAs (circRNAs) are involved in the development of cancers, generally acting as sponges for microRNAs (miRNAs). Here, we screened the circRNA expression profiles of HaCaT cells, which are immortalized human keratinocytes, and arsenite-transformed HaCaT cells (T-HaCaT). The presence of has_circRNA-008913 (circ008913) was confirmed in HaCaT cells. Among the circRNAs down-regulated in T-HaCaT cells, circ008913 showed the greatest decrease and was chosen for further research. In HaCaT cells, arsenite induced increases of mRNA levels of the genes for cell-surface markers (k5 and CD34) of skin stem cells, decreases of DAB2IP, and increases of ZEB1. MicroRNA (miR)-889 suppressed the expression of DAB2IP and was involved in regulation of cancer stem cells (CSCs). Moreover, overexpression of circ008913 with pLCDH-circ008913 or transfection with an miR-889 inhibitor reduced the capacity of T-HaCaT cells for colony formation, invasion, migration, and the sizes of tumors in nude mice, effects that were reversed by co-transfection with an miR-889 mimic. These results suggest that, in HaCaT cells, arsenite decreases circ008913 levels, which act as a sponge for miR-889 and down-regulate the miR-889 target, DAB2IP, which, in turn, up-regulates ZEB1, increases mRNA levels of the cell-surface markers of skin stem cells, and is involved in arsenite-induced acquisition of CSC-like properties that lead to malignant transformation. The results also indicate that circ008913 functions as a competing endogenous RNA (ceRNA) for miR-889, which is involved in the arsenite-induced acquisition of CSC-like properties by regulation of DAB2IP and elucidate a previously unknown mechanism between arsenite-induced acquisition of CSC-like properties and carcinogenesis.

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The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).

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Natural RNA circles function as efficient microRNA sponges.

Thomas B. Hansen, Trine I. Jensen, Bettina H. Clausen … (2014)

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.