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Comprehensive circular RNA expression profiling and competitive endogenous RNAs regulatory networks in distal cholangiocarcinoma

ABSTRACT: To explore the differentially expressed (DE) circular (circ)RNAs, competing endogenous RNAs networks, and potential biomarkers in distal cholangiocarcinoma (dCCA), using microarray analysis, a comprehensive circRNA expression profiling was constructed with six paired dCCA tumor and adjacent normal samples. A total of 171 DE circRNAs were identified. Three upregulated (hsa_circ_0060144, hsa_circ_0008274, and hsa_circ_0000673) and two downregulated circRNAs (hsa_circ_0139402 and hsa_circ_0001714) were validated with RT-qPCR in 40 dCCA patients. Among them, hsa_circ_0000673 had an idea prognostic efficiency (AUC=0.85, p<0.01) and high level of hsa_circ_0000673 was associated with late tumor stage (p<0.01), poor histodifferentiation (p=0.041), and residual tumor (p=0.044). Gene ontology analysis of the host genes of 171 DE circRNAs showed that “response to nutrient”, “adherens junction”, and “cell adhesion molecule binding” were mainly enriched in terms of biological process, cellular component, and molecular functions respectively. Nine target micro(mi)RNAs of the five DE circRNAs were screened out and enriched in cancer associated pathways. Thereafter, 188 DE mRNAs were predicted as target genes of the nine miRNAs. Finally, protein-protein interaction networks were constructed and 20 hubgenes were identified. This research provided a landscape of DE circRNAs in dCCA, constructed circRNA-miRNA-mRNA regulating networks, and identified hsa_circ_0000673 as a potential biomarker and target for treating dCCA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148561 | GEO | 2020/12/31

REPOSITORIES: GEO

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Project description:In platelets, splicing and translation occur in the absence of a nucleus. However, the integrity and stability of mRNAs derived from megakaryocyte progenitor cells remain poorly quantified on a transcriptome-wide level. As circular RNAs (circRNAs) are resistant to degradation by exonucleases, their abundance relative to linear RNAs can be used as a surrogate marker for mRNA stability in the absence of transcription. Here we show that circRNAs are enriched in human platelets 17-188 fold relative to nucleated tissues, and 14-26 fold relative to samples digested with RNAseR to selectively remove linear RNA. We compare RNAseq read depths inside and outside circRNAs to provide in silico evidence of transcript circularity, show that exons within circRNAs are enriched ~13X in platelets relative to nucleated tissues, and identify 3162 genes significantly enriched for circRNAs including some where all RNAs appear to be derived from circular molecules. We also confirm that this is a feature of other anucleate cells through transcriptome sequencing of mature erythrocytes, demonstrate that circRNAs are not enriched in megakaryocytes, and that linear RNAs decay more rapidly than circRNAs in platelet preparations. Collectively, these results suggest that circulating platelets have lost on aveage over 90% of their progenitor mRNAs, and that translation in platelets occurrs against the backdrop of a highly degraded transcriptome. Finally, we find that transcripts classified as products of reverse transcriptase template switching are both enriched in platelets and resistant to decay, countering the recent suggestion that up to 50% of rearranged RNAs are artefacts. A single rRNA depleted total RNA sample was sequenced. This together with 25 publicly available rRNA depleted total RNA samples (including 3 from platelets) were analysed using PTESFinder v 1 (http://sourceforge.net/projects/ptesfinder-v1/) to identify back-splice junctions, characteristic of circRNA transcripts. The contribution of circRNA producing exons was analysed on a gene by gene basis as follows: All circRNA transcripts identified in any sample were first pooled to define exons which can contribute to circRNA generation using custom scripts (available on request). For each sample, expression estimates (RPKMI) across all circRNA producing exons were computed for each locus using the total size of exons (in bp) and the read counts mapping to them. Similarly, total size and exonic read counts for exons for which no circRNA were detected in any sample were used to compute expression estimates (RPKME) for non-circRNA producing exons for each locus. Abundance ratios (RPKMI/RPKME and RPKMI/RPKMI+RPKME) were calculated and compared between Platelets and human tissues using Wilcoxon signed-rank test. Please note that the '25sample_info_accn_no.txt' contains the accession numbers and tissue/cell type information for 25 samples analyzed together.

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Comprehensive circular RNA expression profiling and competitive endogenous RNAs regulatory networks in distal cholangiocarcinoma

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