Silencing of hsa_circ_0004771 inhibits proliferation and induces apoptosis in breast cancer through activation of miR-653 by targeting ZEB2 signaling pathway

Abstract

Background: Circular RNAs (circRNAs) have been reported as the competing endogenous RNAs (ceRNAs) to sponge microRNAs (miRNAs) implicating in the initiation and progression of breast cancer. However, the functions of circRNAs in breast cancer have not been completely clarified. In the present study, we aimed to identify differentially expressed circRNAs in breast cancer tumor tissues, and their roles and downstream targets were investigated in the progression of breast cancer. Methods: High-throughput circRNA sequencing was performed to detect the differentially expressed circRNAs. The CCK-8 and flow cytometry were performed to measure the cell viability and apoptosis in breast cancer cells. Gene and protein expression were assayed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting, respectively. Results: hsa_circ_0004771 and Zinc finger E-box binding homeobox 2 (ZEB2) expression levels were up-regulated and positively correlated in breast cancer tumor tissues. In addition, the expression levels of miR-653 were reduced in breast cancer tumor tissues. We also found that hsa_circ_0004771 functioned as a sponge of miR-653 to inhibit its expression. miR-653 as a post-transcriptional regulator down-regulated the expression of ZEB2 by binding to its 3′-UTR. Interestingly, a significant inverse correlation was observed between miR-653 and hsa_circ_0004771 or ZEB2 expression in breast cancer tumor tissues. Knockdown of hsa_circ_0004771 and ZEB2 served as equally authentic of miR-653 mimics to induce growth inhibition and apoptosis in breast cancer cells. Conclusion: Hsa_circ_0004771/miR-653/ZEB2 regulatory feedback revealed a new molecular mechanism in the pathogenesis of breast cancer, which might provide novel therapeutic targets for the treatment of breast cancer.

<p>Circular RNA circNRIP1 Sponges microRNA-138-5p to Maintain Hypoxia-Induced Resistance to 5-Fluorouracil Through HIF-1α-Dependent Glucose Metabolism in Gastric Carcinoma</p>

“…20 More recent studies by Xie's group demonstrated that silencing of circNRIP1 restrained the proliferation and induced the apoptosis of MCF-7 and MDA-MB-231 cells by regulating the miR-653/Zinc finger E-box binding homeobox 2 axis. 21 Nevertheless, its precise role in hypoxia-induced chemoresistance in GC has never been studied.…”

<p>Biological Roles and Mechanisms of Circular RNA in Human Cancers</p>

“…circ_0004771 acted as a miRNA sponge to decrease expression of miR-653, this in turn targeted mesenchymal marker zinc finger E-box-binding homeobox 2 (ZEB2) gene expression by binding to its 3ʹ-untranslated region (3ʹUTR) of ZEB2 mRNA. 14 In addition, circAGFG1 was correlated with advanced clinical stage, poor prognosis and pathological grade of triple-negative breast cancer patients, mechanistically, circAGFG1 might directly sponge miR-195-5p, which targeted and repressed cyclin E1 expression. 15…”

Long noncoding RNA XIST suppresses tumorigenesis and enhances radiosensitivity in neuroblastoma cells through regulating miR-653-5p/HK2 axis

“…Currently, accumulating evidence demonstrated that aberrant expression miRNA was closely related to the development and progression of cancers, and could affect the cell's response to radiation [18,19]. MiR-653-5p targets 615 transcripts with conserved sites, containing a total of 662 conserved sites and 487 poorly conserved sites, and miR-653-5p can exert regulatory functions in mammalian evolution [20]. MiR-653-5p has been suggested to function as a tumor suppressor or tumor promoter in different cancers [21,22].…”