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Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148736 | GEO | 2020/07/20

REPOSITORIES: GEO

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Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice.

Project description:Naturally occurring circular RNAs efficiently impair miRNA functions. Synthetic circular RNAs may thus serve as potent agents for miRNA inhibition. Their therapeutic effect critically relies on (i) the identification of optimal miRNA targets, (ii) the optimization of decoy structures and (iii) the development of efficient formulations for their use as drugs. In this study, we extensively explored the functional relevance of miR-21-5p in cancer cells. Analyses of cancer transcriptomes reveal that miR-21-5p is the by far most abundant miRNA in human cancers. Deletion of the MIR21 locus in cancer-derived cells identifies several direct and indirect miR-21-5p targets, including major tumor suppressors with prognostic value across cancers. To impair miR-21-5p activities, we evaluate synthetic, circular RNA decoys containing four repetitive binding elements. In cancer cells, these decoys efficiently elevate tumor suppressor expression and impair tumor cell vitality. For their in vivo delivery, we for the first time evaluate the formulation of decoys in polyethylenimine (PEI)-based nanoparticles. We demonstrate that PEI/decoy nanoparticles lead to a significant inhibition of tumor growth in a lung adenocarcinoma xenograft mouse model via the upregulation of tumor suppressor expression. These findings introduce nanoparticle-delivered circular miRNA decoys as a powerful potential therapeutic strategy in cancer treatment.

| S-EPMC8210135 | biostudies-literature

Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice (RNA-Seq)

Project description:Natural and synthetic circular RNAs effectively impair miRNA function. MiR-21-5p is a potent oncomiR presenting ~33% of all miRNAs across cancers, ~41% in lung adenocarcinoma (LUAD), and ~68% in LUAD-derived cells. We validate and identify five main tumor suppressors targeted by miR-21-5p by deletion of the MIR21 locus in LUAD cells. Synthetic, liposome-delivered circular miR-21-5p decoys enhance expression of these tumor suppressors and severely impair tumor cell vitality at low doses. Decoy efficacy is not increased by bulging of miR-21-5p targeting sites, but associated with substantial cellular decoy stability, indicated by a half-life of ~20h. The intraperitoneal application of nanoparticle-delivered miR-21-5p decoys significantly impairs tumor growth in mouse LUAD tumor models. Decoys are well tolerated and were enriched in lung tissue. However, despite low decoy abundance, tumor suppressor expression was only increased in subcutaneous tumors. These findings suggest nanoparticle-delivered circular miRNA decoys as potent therapeutics in cancer treatment.

2020-07-20 | GSE148684 | GEO

Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice (small RNA-Seq II)

2020-07-20 | GSE148735 | GEO

Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice (small RNA-Seq I)

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Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice

Project description:Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice

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Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice (RNA-Seq)

Project description:Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice (RNA-Seq)

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Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice (small RNA-Seq I)

Project description:Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice (small RNA-Seq I)

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Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice (small RNA-Seq II)

Project description:Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice (small RNA-Seq II)

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Synthetic Circular miR-21 Sponge as Tool for Lung Cancer Treatment.

Project description:Lung cancer is the most common cancer in the world and several miRNAs are associated with it. MiRNA sponges are presented as tools to inhibit miRNAs. We designed a system to capture miRNAs based on circular RNAs (circRNA). To demonstrate its usefulness, we chose miR-21, which is upregulated and implicated in lung cancer. We constructed a miR-21 sponge and inserted it into a vector that facilitates circular RNA production (Circ-21) to study its effect on growth, colony formation, and migration in lung cancer cell lines and multicellular tumor spheroids (MTS). Circ-21 induced a significant and time-dependent decrease in the growth of A549 and LL2 cells, but not in L132 cells. Furthermore, A549 and LL2 cells transfected with Circ-21 showed a lower number of colonies and migration than L132. Similar findings were seen in A549 and LL2 Circ-21 MTS, which showed a significant decrease in volume growth, but not in L132 Circ-21 MTS. Based on this, the miR-21 circular sponge may suppress the processes of tumorigenesis and progression. Therefore, our system based on circular sponges seems to be effective, as a tool for the capture of other miRNAs.

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Circular RNA circ-SLC7A6 acts as a tumor suppressor in non-small cell lung cancer through abundantly sponging miR-21.

Project description:Circular RNA (circRNA) is currently considered to be a key regulatory molecule in cancer biology. In the present study, we aimed to explore the functional and clinical roles of circ-SLC7A6 (a circRNA derived from SLC7A6 gene) in non-small cell lung cancer (NSCLC). Circ-SLC7A6 was significantly downregulated in NSCLC tissues in comparison to para-carcinoma tissues. Low circ-SLC7A6 was closely associated with larger tumor size, lymph node metastasis, advanced clinical stage and adverse outcome. Exogenous expression of circ-SLC7A6 evidently inhibited the proliferation and invasion of NSCLC cells. Further investigations revealed that miR-21 was the direct functional target of circ-SLC7A6, in which circ-SLC7A6 abundantly sponged miR-21 and elevated a cohort of tumor suppressors, thus inhibiting NSCLC progression. Interestingly, QKI, elevated by circ-SLC7A6, could directly bind to the introns flanking circ-SLC7A6 to facilitate circ-SLC7A6 production. Importantly, in vivo xenograft tumor experiments showed that reintroduction of circ-SLC7A6 retarded tumor growth as well as decreased lung metastatic nodules. Overall, our study demonstrates that circ-SLC7A6 is a novel tumor suppressor in NSCLC, targeting circ-SLC7A6/miR-21 axis may be a promising treatment for NSCLC patients.

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