Abstract
BackgroundCircular RNAs (circRNAs) have been considered to mediate occurrence and development of human cancers, generally acting as microRNA (miRNA) sponges to regulate downstream genes expression. However, the aberrant expression profile and dysfunction of circRNAs in human bladder cancer remain to be investigated. The present study aims to elucidate the potential role and molecular mechanism of circACVR2A in regulating the proliferation and metastasis of bladder cancer.MethodscircACVR2A (hsa_circ_0001073) was identified by RNA-sequencing and validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. The role of circACVR2A in bladder cancer was assessed both in vitro and in vivo. Biotin-coupled probe pull down assay, biotin-coupled microRNA capture, dual-luciferase reporter assay, and fluorescence in situ hybridization were conducted to evaluate the interaction between circACVR2A and microRNAs.ResultsThe expression of circACVR2A was lower in bladder cancer tissues and cell lines. The down-regulation of circACVR2A was positively correlated with aggressive clinicopathological characteristics, and circACVR2A served as an independent risk factor for overall survival in bladder cancer patients after cystectomy. Our in vivo and in vitro data indicated that circACVR2A suppressed the proliferation, migration and invasion of bladder cancer cells. Mechanistically, we found that circACVR2A could directly interact with miR-626 and act as a miRNA sponge to regulate EYA4 expression.ConclusionscircACVR2A functions as a tumor suppressor to inhibit bladder cancer cell proliferation and metastasis through miR-626/EYA4 axis, suggesting that circACVR2A is a potential prognostic biomarker and therapeutic target for bladder cancer.
Highlights
Circular RNAs have been considered to mediate occurrence and development of human cancers, generally acting as microRNA sponges to regulate downstream genes expression
Since circRNAs don’t have 3′ polyadenylated tail, we detected the existence of circACVR2A in the reverse transcription products using random primers or oligo dT primers, and we verified that circACVR2A was almost undetectable when oligo-dT primers were used (Fig. 1c)
CircACVR2A was only detectable in cDNA but not genomic DNA from T24 and UM-UC-3 cell lines by quantitative real-time polymerase chain reaction (qRT-PCR) with divergent primers, while Activin A receptor type 2A (ACVR2A) could be amplified in both cDNA and gDNA using convergent primers (Fig. 1d)
Summary
Circular RNAs (circRNAs) have been considered to mediate occurrence and development of human cancers, generally acting as microRNA (miRNA) sponges to regulate downstream genes expression. The present study aims to elucidate the potential role and molecular mechanism of circACVR2A in regulating the proliferation and metastasis of bladder cancer. Emerging evidence indicates that circRNAs are involved in the regulation of gene transcription and translation, and in the cytoplasm and nuclear localization of proteins, suggesting that they may participate in the progression of many diseases, including cancers. CircRNAs can function as microRNA (miRNA) sponges, RNA-binding protein sponges and protein-coding genes. Several circRNAs have been reported to be aberrantly expressed in BC cell lines and tissues, and they regulate proliferation, apoptosis, metastasis and epithelial-mesenchymal transition (EMT) [16,17,18,19]. The biological functions and clinical significance of circRNAs implicated in BC remain largely unknown
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