Dataset Information

The Role of Circular RNA CDR1as/ciRS-7 in Regulating Tumor Microenvironment: A Pan-Cancer Analysis.

ABSTRACT: Circular RNA CDR1as/ciRS-7 functions as an oncogenic regulator in various cancers. However, there has been a lack of systematic and comprehensive analysis to further elucidate its underlying role in cancer. In the current study, we firstly performed a bioinformatics analysis of CDR1as among 868 cancer samples by using RNA-seq datasets of the MiOncoCirc database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), CIBERSORT, Estimating the Proportion of Immune and Cancer cells (EPIC), and the MAlignant Tumors using Expression data (ESTIMATE) algorithm were applied to investigate the underlying functions and pathways. Functional enrichment analysis suggested that CDR1as has roles associated with angiogenesis, extracellular matrix (ECM) organization, integrin binding, and collagen binding. Moreover, pathway analysis indicated that it may regulate the TGF-? signaling pathway and ECM-receptor interaction. Therefore, we used CIBERSORT, EPIC, and the ESTIMATE algorithm to investigate the association between CDR1as expression and the tumor microenvironment. Our data strongly suggest that CDR1as may play a specific role in immune and stromal cell infiltration in tumor tissue, especially those of CD8+ T cells, activated NK cells, M2 macrophages, cancer-associated fibroblasts (CAFs) and endothelial cells. Generally, systematic and comprehensive analyses of CDR1as were conducted to shed light on its underlying pro-cancerous mechanism. CDR1as regulates the TGF-? signaling pathway and ECM-receptor interaction to serve as a mediator in alteration of the tumor microenvironment.

SUBMITTER: Zou Y

PROVIDER: S-EPMC6770779 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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The Role of Circular RNA CDR1as/ciRS-7 in Regulating Tumor Microenvironment: A Pan-Cancer Analysis.

Zou Yutian Y Zheng Shaoquan S Deng Xinpei X Yang Anli A Xie Xinhua X Tang Hailin H Xie Xiaoming X

Biomolecules 20190830 9

Circular RNA CDR1as/ciRS-7 functions as an oncogenic regulator in various cancers. However, there has been a lack of systematic and comprehensive analysis to further elucidate its underlying role in cancer. In the current study, we firstly performed a bioinformatics analysis of CDR1as among 868 cancer samples by using RNA-seq datasets of the MiOncoCirc database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), CIBERSORT, Estimating the Prop ...[more]

PMID: 31480381

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Project description:T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), an immune checkpoint, plays a pivotal role in immune suppression. However its role in tumor immunity and correlation with the genetic and epigenetic alterations remains unknown. Here, we comprehensively analyzed the expression patterns of the TIGIT and its value of prognostic prediction among 33 types of cancers based on the data collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects (GTEx). Furthermore, the correlations of TIGIT with pathological stages, tumor-infiltrating immune cells (TIICs), signatures of T cells subtypes, immune checkpoint genes, the degree of Estimation of STromal and Immune cells in MAlignant Tumor tissues using the Expression data (ESTIMATE), tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, and DNA methyltransferases (DNMTs) were also explored. Gene functional enrichment was conducted by Gene Set Enrichment Analysis (GSEA). Our results showed that the expression of TIGIT was upregulated in most of the cancer types. Cox regression model showed that high expression of TIGIT in tumor samples correlates with poor prognosis in KIRC, KIRP, LGG, UVM, and with favorable prognosis in BRCA, CECS, HNSC, SKCM. TIGIT expression positively correlated with advanced stages, TIICs, the signatures of effector T cells, exhausted T cells, effector Tregs and the degree of ESTIMATE in KIRC, KIRP and UVM. TIGIT expression also positively correlated with CTLA4, PDCD1 (PD-1), CD274 (PD-L1), ICOS in most of the cancer types. Furthermore, the expression of TIGIT was correlated with TMB, MSI, MMR genes and DNMTs in different types of cancers. GSEA analysis showed that the expression of TIGIT was related to cytokine-cytokine receptor interaction, allograft rejection, oxidative phosphorylation. These findings suggested that TIGIT could serve as a potential biomarker for prognosis and a novel target for immunotherapies in cancers.

Project description:BACKGROUND:Inactivation of the tumor suppressor p53 is critical for pathogenesis of glioma, in particular glioblastoma multiforme (GBM). MDM2, the main negative regulator of p53, binds to and forms a stable complex with p53 to regulate its activity. Hitherto, it is unclear whether the stability of the p53/MDM2 complex is affected by lncRNAs, in particular circular RNAs that are usually abundant and conserved, and frequently implicated in different oncogenic processes. METHODS:RIP-seq and RIP-qPCR assays were performed to determine the most enriched lncRNAs (including circular RNAs) bound by p53, followed by bioinformatic assays to estimate the relevance of their expression with p53 signaling and gliomagenesis. Subsequently, the clinical significance of CDR1as was evaluated in the largest cohort of Chinese glioma patients from CGGA (n?=?325), and its expression in human glioma tissues was further evaluated by RNA FISH and RT-qPCR, respectively. Assays combining RNA FISH with protein immunofluorescence were performed to determine co-localization of CDR1as and p53, followed by CHIRP assays to confirm RNA-protein interaction. Immunoblot assays were carried out to evaluate protein expression, p53/MDM2 interaction and p53 ubiquitination in cells in which CDR1as expression was manipulated. After AGO2 or Dicer was knocked-down to inhibit miRNA biogenesis, effects of CDR1as on p53 expression, stability and activity were determined by immunoblot, RT-qPCR and luciferase reporter assays. Meanwhile, impacts of CDR1as on DNA damage were evaluated by flow cytometric assays and immunohistochemistry. Tumorigenicity assays were performed to determine the effects of CDR1as on colony formation, cell proliferation, the cell cycle and apoptosis (in vitro), and on tumor volume/weight and survival of nude mice xenografted with GBM cells (in vivo). RESULTS:CDR1as is found to bind to p53 protein. CDR1as expression decreases with increasing glioma grade and it is a reliable independent predictor of overall survival in glioma, particularly in GBM. Through a mechanism independent of acting as a miRNA sponge, CDR1as stabilizes p53 protein by preventing it from ubiquitination. CDR1as directly interacts with the p53 DBD domain that is essential for MDM2 binding, thus disrupting the p53/MDM2 complex formation. Induced upon DNA damage, CDR1as may preserve p53 function and protect cells from DNA damage. Significantly, CDR1as inhibits tumor growth in vitro and in vivo, but has little impact in cells where p53 is absent or mutated. CONCLUSIONS:Rather than acting as a miRNA sponge, CDR1as functions as a tumor suppressor through binding directly to p53 at its DBD region to restrict MDM2 interaction. Thus, CDR1as binding disrupts the p53/MDM2 complex to prevent p53 from ubiquitination and degradation. CDR1as may also sense DNA damage signals and form a protective complex with p53 to preserve p53 function. Therefore, CDR1as depletion may play a potent role in promoting tumorigenesis through down-regulating p53 expression in glioma. Our results broaden further our understanding of the roles and mechanism of action of circular RNAs in general and CDR1as in particular, and can potentially open up novel therapeutic avenues for effective glioma treatment.

Dataset Information

The Role of Circular RNA CDR1as/ciRS-7 in Regulating Tumor Microenvironment: A Pan-Cancer Analysis.

Publications

The Role of Circular RNA CDR1as/ciRS-7 in Regulating Tumor Microenvironment: A Pan-Cancer Analysis.

Similar Datasets

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