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Circular RNA

Circular RNA (or circRNA) is a type of single-stranded RNA which, unlike the better known linear RNA, forms a covalently closed continuous loop, i.e., in circular RNA the 3' and 5' ends normally present in an RNA molecule have been joined together. This feature confers numerous properties to circular RNAs, many of which have only recently been identified.

Circular RNAs (circRNAs) are widespread throughout the eukaryotic genome. The expression of circRNAs is regulated by both cis-elements and trans-factors, and the expression pattern of circRNAs is cell type- and disease-specific.

Similar to other types of non-coding RNAs, functions of circRNAs are also versatile. CircRNAs have been reported previously to function as microRNA (miRNA) sponges, protein sponges, coding RNAs, or scaffolds for protein complexes.

Increasing evidence has confirmed that circRNAs are involved in regulating the development and progression of various tumors.

Several circRNAs have been reported to play important roles in human malignancies, including glioma.

Liu et al. reviewed several reports related to circRNAs and glioma, as well as the potential diagnostic and therapeutic applications of circRNAs in brain cancer. In general, some circRNAs, such as circSMARCA5 and circCFH, are found to be expressed in a glioma-specific pattern, these circRNAs may be used as tumor biomarkers. In addition, some circRNAs have been found to play oncogenic roles in glioma (e.g., circNFIX and circNT5E), whereas others have been reported to function as tumor suppressors (e.g., circFBXW7 and circSHPRH). Furthermore, circRNA is a good tool for protein expression because of its higher stability compared to linear RNAs. Thus, circRNAs may also be an ideal choice for gene/protein delivery in future brain cancer therapies. There are some challenges in circRNA research in glioma and other diseases. Research related to circRNAs in glioma is comparatively new and many mysteries remain to be solved 1).

The aim of this study is to explore the biological roles and underlying mechanisms of circRNA vacuolar protein sorting 18 homolog (circVPS18) in glioblastoma. A quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the expression of circVPS18, microRNA (miR)-1299-3p, and branched-chain amino acid transaminase 1 (BCAT1). In vitro experiments were conducted using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and tube formation assays, respectively. Western blot was conducted to examine all protein levels. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to confirm the interaction between miR-1229-3p and circVPS18 or BCAT1. The murine xenograft model was established to conduct in vivo assay. CircVPS18 and BCAT1 were highly expressed while miR-1229-3p was lowly expressed in glioblastoma tissues and cells. CircVPS18 knockdown inhibited glioblastoma progression by inhibiting cell proliferation, migration, invasion, and angiogenesis, and promoting cell apoptosis. Moreover, miR-1229-3p could be targeted by circVPS18; inhibition of miR-1229-3p could invert the suppressive effect of circVPS18 knockdown on glioblastoma tumorigenesis. Furthermore, BCAT1 was a target of miR-1229-3p; functionally, BCAT1 overexpression could reverse the inhibitory effects of miR-1229-3p upregulation on glioblastoma cell malignant phenotypes. Moreover, we also verified that circVPS18A could regulate BCAT1 expression by sponging miR-1229-3p. Additionally, circVPS18 silencing also restrained tumor growth and metastasis in vivo. CircVPS18 accelerated glioblastoma progression by miR-1229-3p/BCAT1 axis, providing a potential therapeutic target for glioblastoma 2).

The aim of a study of Gao et al. from the Department of Neurosurgery, People's Hospital of Lanling County, Linyi, Shandong, China was to examine the effect of circFBXW7 on glioma progression and to determine its underlying mechanism.

qRT-PCR was performed to measure the expression of circFBXW7, miR 23a-3p, and PTEN in tissues and cell lines of glioma. The proliferation ability of glioma cells was examined using the CCK-8 assay. Glioma cell migration and invasion capacity were detected using Transwell assays. The dual-luciferase reporter gene assay was employed to examine the correlation between miR-23a-3p and circFBXW7 or PTEN. The expression levels of the related genes were determined using western blotting analysis. A glioma xenograft tumor model was employed to evaluate the functional roles of circFBXW7 in vivo.

CircFBXW7 was found to be aberrantly downregulated in glioma tumor tissues and cell lines. Overexpression of circFBXW7 was found to significantly inhibit the proliferation, migration, and invasion ability of the glioma cells. Moreover, bioinformatic analysis and dual-luciferase reporter assays confirmed that circFBXW7 can directly target miR-23a-3p, which then blocks the binding of miR-23a-3p to the 3' untranslated region (UTR) of PTEN. Mechanically, circFBXW7 suppresses cell proliferation and metastases in glioma by sponging miR-23a-3p, resulting in elevated PTEN expression. In addition, in vivo experiments also confirmed that circFBXW7 overexpression effectively halts tumor growth and metastases. Consistent with the in vitro observations, circFBXW7 overexpression significantly decreased miR-23a-3p, Ki-67, and N-cadherin, as well as increased PTEN and E-cadherin levels.

The results revealed that circFBXW7 exhibits anti-proliferative and anti-metastases activities via sponging miR-23a-3p to elevate PTEN expression in glioma, which may offer a novel target for clinical therapy and diagnosis of glioma 3).

Accumulating evidence indicates that the circRNA/Wnt axis modulates the expression of cancer genes and then regulates cancer progression. Wnt pathway-related circRNA expression is obviously associated with many clinical characteristics. CircRNAs could regulate cell biological functions by interacting with the Wnt pathway. Moreover, Wnt pathway-related circRNAs are promising potential biomarkers for cancer diagnosis, prognosis evaluation, and cancer treatment 4).

Liu J, Zhao K, Huang N, Zhang N. Circular RNAs and human glioma. Cancer Biol Med. 2019 Feb;16(1):11-23. doi: 10.20892/j.issn.2095-3941.2018.0425. PubMed PMID: 31119043; PubMed Central PMCID: PMC6528446.
Huang Q, Li W, Huang Y, Chen Q, Wei W. Circular RNA VPS18 Promotes Glioblastoma Progression by Regulating miR-1229-3p/BCAT1 Axis. Neurotox Res. 2022 Jul 1. doi: 10.1007/s12640-022-00530-6. Epub ahead of print. PMID: 35776379.
Gao ZG, Yang P, Huang J, Ding YQ. CircFBXW7 Alleviates Glioma Progression through Regulating MiR-23a-3p/PTEN Axis. Anat Rec (Hoboken). 2020 May 4. doi: 10.1002/ar.24410. [Epub ahead of print] PubMed PMID: 32365279.
Xue C, Li G, Zheng Q, Gu X, Bao Z, Lu J, Li L. The functional roles of the circRNA/Wnt axis in cancer. Mol Cancer. 2022 May 5;21(1):108. doi: 10.1186/s12943-022-01582-0. PMID: 35513849.
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