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Journal ArticleDOI: 10.1038/S41556-021-00639-4

Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling.

04 Mar 2021-Nature Cell Biology (Nature Publishing Group)-Vol. 23, Iss: 3, pp 278-291
Abstract: Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.

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Topics: Circular RNA (52%)
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27 results found


Open accessJournal ArticleDOI: 10.3390/CANCERS13112748
01 Jun 2021-Cancers
Abstract: The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms.

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6 Citations


Open accessJournal ArticleDOI: 10.1186/S12943-021-01417-4
Lian He1, Changfeng Man1, Shouyan Xiang1, Lin Yao1  +2 moreInstitutions (2)
15 Sep 2021-Molecular Cancer
Abstract: Circular RNAs a kind of covalently closed RNA and widely expressed in eukaryotes. CircRNAs are involved in a variety of physiological and pathological processes, but their regulatory mechanisms are not fully understood. Given the development of the RNA deep-sequencing technology and the improvement of algorithms, some CircRNAs are discovered to encode proteins through the cap-independent mechanism and participate in the important process of tumorigenesis and development. Based on an overview of CircRNAs, this paper summarizes its translation mechanism and research methods, and reviews the research progress of CircRNAs translation in the field of oncology in recent years. Moreover, this paper aims to provide new ideas for tumor diagnosis and treatment through CircRNAs translation.

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Topics: Circular RNA (53%)

4 Citations


Open accessPosted ContentDOI: 10.1101/2021.03.16.435594
Liang Qu1, Zongyi Yi1, Yong Shen1, Yiyuan Xu1  +11 moreInstitutions (2)
16 Mar 2021-bioRxiv
Abstract: SARS-CoV-2 has caused a worldwide pandemic. The emerging variants B.1.1.7 in the UK, B.1.351 in South Africa, and P.1 in Brazil have recently spread rapidly, arousing concerns about the efficacy of the current vaccines and antibody therapies. Therefore, there is still a high demand for alternative vaccines with great efficacy, high design flexibility, and fast manufacturing speed. Here, we reported a circular RNA (circRNA) vaccine that encodes the trimeric RBD of SARS-CoV-2 spike protein. Being a circularized RNA molecule, circRNARBD could be rapidly produced via in vitro transcription and is highly stable without nucleotide modification. Lipid-nanoparticle-encapsulated circRNARBD elicited potent and sustained neutralizing antibodies, as well as Th1-biased T cell responses in mice. Notably, antibodies from mice immunized with circRNA encoding RBD variant (K417N-E484K-501Y) effectively neutralized B.1.351 variant. Moreover, we developed therapeutic circRNAs, encoding SARS-CoV-2 neutralizing nanobodies or hACE2 decoys, which could effectively neutralize SARS-CoV-2 pseudovirus. Our study suggests that circular RNA holds the potential to become a novel vaccine and therapeutic platform.

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Topics: Circular RNA (56%)

3 Citations


Journal ArticleDOI: 10.1016/J.SEMCDB.2021.04.002
Abstract: Groundbreaking discoveries in molecular oncology have leveraged our understanding altogether to a new level. Mapping of plethora of cell signaling pathways has enabled researchers to drill down deep into the intermeshed regulatory networks which crosstalk to promote carcinogenesis and metastasis. More importantly, discovery of non-coding RNAs has added new layers of complexity to already complicated nature of cell signaling pathways. The discovery of circular RNAs (circRNAs) has opened the door to an ever-widening understanding of cellular processes that are controlled or influenced by circRNAs. In this review, we have summarized most recent advancements in our understanding related to interplay between circular RNAs and microRNAs for the regulation of NOTCH, Wnt/β-catenin, Hippo, SHH/GLI, JAK/STAT and TGF/SMAD pathways in different cancers.

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Topics: Wnt signaling pathway (55%), microRNA (50%), Catenin (50%)

2 Citations


Journal ArticleDOI: 10.1016/J.CANLET.2021.09.030
Binghong Chen1, Mengying Wang1, Renhua Huang1, Keman Liao1  +9 moreInstitutions (3)
25 Sep 2021-Cancer Letters
Abstract: Glioblastoma (GBM) is one of the most devastating cancers and is characterized by rapid cell proliferation and aggressive invasiveness. Legumain (LGMN), a substrate-specific protease, is associated with poor progression of GBM. Circular RNAs (circRNAs) are aberrantly expressed in various cancers and play crucial roles in tumor progression; however, the functional roles of circRNAs originating from LGMN remain largely unknown in GBM. Herein, we found that hsa_circ_0033009 (circLGMN) was the most abundantly expressed circRNA derived from LGMN. CircLGMN was upregulated in high-grade glioma (HGG), and high expression of circLGMN was associated with poor prognosis in patients with glioma. CircLGMN overexpression promoted GBM cell proliferation and enhanced cell invasion. Mechanistically, circLGMN acts as a sponge for miR-127-3p, and prevents miR-127-3p-mediated degradation of LGMN mRNA, ultimately leading to increased LGMN protein expression. Treatment with miR-127-3p mimic suppressed proliferation and reduced invasion of GBM cells overexpressing circLGMN. Moreover, circLGMN overexpression promoted GBM malignancy in vivo, while miR-127-3p overexpression alleviated this effect. Taken together, circLGMN is a novel tumor-promoting circRNA that acts by sponging miR-127-3p, which ultimately leads to LGMN upregulation. Thus, targeting the circLGMN/miR-127-3p/LGMN axis might be a promising strategy for GBM treatment. More importantly, the discovery of the self-regulatory mechanism of LGMN expression by circLGMN, will facilitate further research on LGMN.

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Topics: Tumor progression (54%)

2 Citations


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63 results found


Journal ArticleDOI: 10.1038/NATURE05236
Shideng Bao1, Qiulian Wu, Roger E. McLendon, Yueling Hao  +5 moreInstitutions (1)
07 Dec 2006-Nature
Abstract: Ionizing radiation represents the most effective therapy for glioblastoma (World Health Organization grade IV glioma), one of the most lethal human malignancies, but radiotherapy remains only palliative because of radioresistance. The mechanisms underlying tumour radioresistance have remained elusive. Here we show that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The fraction of tumour cells expressing CD133 (Prominin-1), a marker for both neural stem cells and brain cancer stem cells, is enriched after radiation in gliomas. In both cell culture and the brains of immunocompromised mice, CD133-expressing glioma cells survive ionizing radiation in increased proportions relative to most tumour cells, which lack CD133. CD133-expressing tumour cells isolated from both human glioma xenografts and primary patient glioblastoma specimens preferentially activate the DNA damage checkpoint in response to radiation, and repair radiation-induced DNA damage more effectively than CD133-negative tumour cells. In addition, the radioresistance of CD133-positive glioma stem cells can be reversed with a specific inhibitor of the Chk1 and Chk2 checkpoint kinases. Our results suggest that CD133-positive tumour cells represent the cellular population that confers glioma radioresistance and could be the source of tumour recurrence after radiation. Targeting DNA damage checkpoint response in cancer stem cells may overcome this radioresistance and provide a therapeutic model for malignant brain cancers.

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Topics: Radioresistance (67%), Cancer stem cell (60%), G2-M DNA damage checkpoint (60%) ... show more

5,242 Citations


Journal ArticleDOI: 10.1038/NATURE11928
21 Mar 2013-Nature
Abstract: Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.

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Topics: Circular RNA (57%), RNA (52%), RNA splicing (52%) ... show more

4,462 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2013.09.034
Cameron Brennan1, Roel G.W. Verhaak, Aaron McKenna2, Benito Campos3  +54 moreInstitutions (27)
10 Oct 2013-Cell
Abstract: We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

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Topics: Mesenchymal Glioblastoma (54%), DNA methylation (53%), PDGFRA (51%) ... show more

2,850 Citations


Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTY560
Shifu Chen1, Yanqing Zhou, Yaru Chen, Jia Gu1Institutions (1)
01 Sep 2018-Bioinformatics
Abstract: Motivation Quality control and preprocessing of FASTQ files are essential to providing clean data for downstream analysis. Traditionally, a different tool is used for each operation, such as quality control, adapter trimming and quality filtering. These tools are often insufficiently fast as most are developed using high-level programming languages (e.g. Python and Java) and provide limited multi-threading support. Reading and loading data multiple times also renders preprocessing slow and I/O inefficient. Results We developed fastp as an ultra-fast FASTQ preprocessor with useful quality control and data-filtering features. It can perform quality control, adapter trimming, quality filtering, per-read quality pruning and many other operations with a single scan of the FASTQ data. This tool is developed in C++ and has multi-threading support. Based on our evaluation, fastp is 2-5 times faster than other FASTQ preprocessing tools such as Trimmomatic or Cutadapt despite performing far more operations than similar tools. Availability and implementation The open-source code and corresponding instructions are available at https://github.com/OpenGene/fastp.

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Topics: FASTQ format (65%), Preprocessor (50%)

2,501 Citations


Open accessJournal ArticleDOI: 10.1371/JOURNAL.PONE.0030733
Julia Salzman1, Charles Gawad1, Peter L. Wang1, Norman J. Lacayo1  +1 moreInstitutions (1)
01 Feb 2012-PLOS ONE
Abstract: Most human pre-mRNAs are spliced into linear molecules that retain the exon order defined by the genomic sequence. By deep sequencing of RNA from a variety of normal and malignant human cells, we found RNA transcripts from many human genes in which the exons were arranged in a non-canonical order. Statistical estimates and biochemical assays provided strong evidence that a substantial fraction of the spliced transcripts from hundreds of genes are circular RNAs. Our results suggest that a non-canonical mode of RNA splicing, resulting in a circular RNA isoform, is a general feature of the gene expression program in human cells.

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Topics: Circular RNA (67%), Intron (66%), Non-coding RNA (63%) ... show more

1,587 Citations


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