Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations

Guarnerio, Jlenia; Bezzi, Marco; Jeong, Jong Cheol; Paffenholz, Stella V; Berry, Kelsey; Naldini, Matteo Maria; Lo‐Coco, Francesco; Tay, Yvonne; Beck, Andrew H.; Pandolfi, Pier Paolo

doi:10.1016/j.cell.2016.07.035

Cited by 186 publications

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“…CircRNAs are reportedly expressed in a spatial- and temporal-specific manner [10, 11]. A growing body of research suggests that circRNAs participate in embryonic development, cellular activities, and many human diseases [12, 13]. However, few studies have focused on the relationship between circRNAs and osteoblastic differentiation of stem cells.…”

Section: Introductionmentioning

confidence: 99%

Circular RNA CDR1as regulates osteoblastic differentiation of periodontal ligament stem cells via the miR-7/GDF5/SMAD and p38 MAPK signaling pathway

et al. 2018

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BackgroundPeriodontal ligament stem cells (PDLSCs) are considered as candidate cells for the regeneration of periodontal and alveolar bone tissues. Antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), which is a newly discovered circular RNA (circRNA), has been reported to act as an miR-7 sponge and to be involved in many biological processes. Here, we investigated the potential roles of CDR1as and miR-7 in the osteogenic differentiation of PDLSCs.MethodsThe expression pattern of CDR1as and miR-7 in PDLSCs during osteogenesis was detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Then we overexpressed or knocked down CDR1as or miR-7 to confirm whether they were involved in the regulation of osteoblast differentiation in PDLSCs. Alkaline phosphatase (ALP) and alizarin red S (ARS) staining were used to detect the activity of osteoblasts and mineral deposition. Furthermore, a dual luciferase reporter assay was conducted to analyze the binding of miR-7 to growth differentiation factor (GDF)5. To further verify the role of CDR1as in osteoblast differentiation, we conducted animal experiments in vivo. New bone formation in specimens was analyzed by microcomputed tomography (micro-CT), hematoxylin and eosin staining, and immunofluorescence staining.ResultsWe observed that CDR1as was significantly upregulated during the osteogenic differentiation, whereas miR-7 was significantly downregulated. Moreover, knockdown of CDR1as and overexpression of miR-7 inhibited the ALP activity, ARS staining, and expression of osteogenic genes. Overexpression of miR-7 significantly reduced the activity of luciferase reporter vectors containing the wild-type, but not the mutant, 3’ untranslated region (UTR) sequence of GDF5. Furthermore, knockdown of GDF5 partially reversed the effects of miR-7 inhibitor on osteoblast differentiation. Downregulation of CDR1as or GDF5 subsequently inhibited phosphorylation of Smad1/5/8 and p38 mitogen-activated protein kinases (MAPK), while upregulation of miR-7 decreased the level of phosphorylated Smad1/5/8 and p38 MAPK. In vivo, CDR1as knockdown lead to less bone formation compared with the control group as revealed by micro-CT and the histological analysis.ConclusionsOur results demonstrated that CDR1as acts as a miR-7 inhibitor, triggering the upregulation of GDF5 and subsequent Smad1/5/8 and p38 MAPK phosphorylation to promote osteogenic differentiation of PDLSCs. This study provides a novel understanding of the mechanisms of osteogenic differentiation, and suggests a potential method for promoting bone formation.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0976-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Circular RNA CDR1as regulates osteoblastic differentiation of periodontal ligament stem cells via the miR-7/GDF5/SMAD and p38 MAPK signaling pathway

et al. 2018

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“…However, most circRNAs are found in the cytoplasm, in which, intronic lariat species of circRNAs can interact directly with proteins (15). Fusion circRNAs arise from translocated chromosomal regions and are involved in proliferation and tumorigenesis (16). Among the numerous effects of circRNAs, 1 crucial function is their activity as microRNA (miRNA) sponges, where they can bind to miRNAs and act as natural miRNA sponges to inhibit the miRNAs' regulatory actions (17,18).…”

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confidence: 99%

Silica‐induced initiation of circular ZC3H4 RNA/ZC3H4 pathway promotes the pulmonary macrophage activation

et al. 2018

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Phagocytosis of silicon dioxide (SiO) into lung cells causes an inflammatory cascade that results in fibroblast proliferation and migration, followed by fibrosis. Circular RNAs (circRNAs) are a subclass of noncoding RNAs that are present within mammalian cells; however, researchers have not determined whether circRNAs are involved in the pathophysiologic process of silicosis. To elucidate the role of these RNAs in SiO-induced inflammation in pulmonary macrophages, we investigated the upstream molecular mechanisms and functional effects of circRNAs on cell apoptosis, proliferation, and migration. Primary cultures of alveolar macrophages from healthy donors and from patients and the RAW264.7 macrophage cell line were used to explore the functions of circZC3H4 RNA in macrophage activation. The experimental results indicated the following: 1) SiO concomitantly increased circZC3H4 RNA expression and increased ZC3H4 protein levels; 2) circular ZC3H4 (circZC3H4) RNA and ZC3H4 protein participated in SiO-induced macrophage activation; and 3) SiO-activated macrophages promoted fibroblast proliferation and migration via the circZC3H4 RNA/ZC3H4 pathway. The up-regulation of the ZC3H4 protein was confirmed in tissue samples from patients with silicosis. Our study elucidates a link between SiO-induced macrophage activation and the circZC3H4 RNA/ZC3H4 pathway, thereby providing novel insight into the potential use of ZC3H4 to develop novel therapeutic strategies for silicosis.-Yang, X., Wang, J., Zhou, Z., Jiang, R., Huang, J., Chen, L., Cao, Z., Chu, H., Han, B., Cheng, Y., Chao, J. Silica-induced initiation of circular ZC3H4 RNA/ZC3H4 pathway promotes the pulmonary macrophage activation.

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“…Second, in endogenous condition, disruption of intronic RNA pairing by CRISPR-Cas9 mediated genome editing resulted in the depletion of circRNA expression, while the linear mRNA counterpart remains largely unchanged [24]. Finally, distal intronic sequences from different genes could also be juxtaposed after gene fusion to form RNA pairing that flanks the breakpoint of fusion genes, leading to the formation of aberrant fusion-circRNAs in cancer cells [28].…”

Section: General Regulatory Role Of Complementary Sequences On Circrnmentioning

confidence: 99%

Multifaceted roles of complementary sequences on circRNA formation

Yang¹,

Wang²,

Yang

2017

Quant. Biol.

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Background: Circular RNAs (circRNAs) from back-spliced exon(s) are characterized by the covalently closed loop feature with neither 5′ to 3′ polarity nor polyadenylated tail. By using specific computational approaches that identify reads mapped to back-splice junctions with a reversed genomic orientation, ten thousands of circRNAs have been recently re-identified in various cell lines/tissues and across different species. Increasing lines of evidence suggest that back-splicing is catalyzed by the canonical spliceosomal machinery and modulated by cis-elements and trans-factors. Results: In this mini-review, we discuss our current understanding of circRNA biogenesis regulation, mainly focusing on the complex regulation of complementary sequences, especially Alus in human, on circRNA formation. Conclusions: Back-splicing can be significantly facilitated by RNA pair formed by orientation-opposite complementary sequences that juxtapose flanking introns of circularized exon(s). RNA pair formed within individual introns competes with RNA pair formed across flanking introns in the same gene locus, leading to distinct choices for either canonical splicing or back-splicing. Multiple RNA pairs that bracket different circle-forming exons compete for alternative back-splicing selection, resulting in multiple circRNAs generated in a single gene locus.

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Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations

Cited by 186 publications

References 0 publications

Circular RNA CDR1as regulates osteoblastic differentiation of periodontal ligament stem cells via the miR-7/GDF5/SMAD and p38 MAPK signaling pathway

Circular RNA CDR1as regulates osteoblastic differentiation of periodontal ligament stem cells via the miR-7/GDF5/SMAD and p38 MAPK signaling pathway

Silica‐induced initiation of circular ZC3H4 RNA/ZC3H4 pathway promotes the pulmonary macrophage activation

Multifaceted roles of complementary sequences on circRNA formation

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