Dataset Information

CeRNA regulatory network-based analysis to study the roles of noncoding RNAs in the pathogenesis of intrahepatic cholangiocellular carcinoma.

ABSTRACT: To explore and understand the competitive mechanism of ceRNAs in intrahepatic cholangiocarcinoma (ICC), we used bioinformatics analysis methods to construct an ICC-related ceRNA regulatory network (ceRNET), which contained 340 lncRNA-miRNA-mRNA regulatory relationships based on the RNA expression datasets in the NCBI GEO database. We identified the core regulatory pathway RP11-328K4.1-hsa-miR-27a-3p-PROS1, which is related to ICC, for further validation by molecular biology assays. GO analysis of 44 differentially expressed mRNAs in ceRNET revealed that they were mainly enriched in biological processes including "negative regulation of epithelial cell proliferation" and "positive regulation of activated T lymphocyte proliferation." KEGG analysis showed that they were mainly enriched in the "complement and coagulation cascade" pathway. The molecular biology assay showed that lncRNA RP11-328K4.1 expression was significantly lower in the cancerous tissues and peripheral plasma of ICC patients than in normal controls (p<0.05). In addition, hsa-miR-27a-3p was found to be significantly upregulated in the cancer tissues and peripheral plasma of ICC patients (p<0.05). Compared to normal controls, the expression of PROS1 mRNA was significantly downregulated in ICC patient cancer tissues (p<0.05) but not in peripheral plasma (p>0.05). Furthermore, ROC analysis revealed that RP11-328K4.1, hsa-miR-27a-3p, and PROS1 had significant diagnostic value in ICC. We concluded that the upregulation of lncRNA RP11-328K4.1, which might act as a miRNA sponge, exerts an antitumor effect in ICC by eliminating the inhibition of PROS1 mRNA expression by oncogenic miRNA hsa-miR-27a.

SUBMITTER: Xu W

PROVIDER: S-EPMC7053603 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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CeRNA regulatory network-based analysis to study the roles of noncoding RNAs in the pathogenesis of intrahepatic cholangiocellular carcinoma.

Xu Weiyu W Yu Si S Xiong Jianping J Long Junyu J Zheng Yongchang Y Sang Xinting X

Aging 20200117 2

To explore and understand the competitive mechanism of ceRNAs in intrahepatic cholangiocarcinoma (ICC), we used bioinformatics analysis methods to construct an ICC-related ceRNA regulatory network (ceRNET), which contained 340 lncRNA-miRNA-mRNA regulatory relationships based on the RNA expression datasets in the NCBI GEO database. We identified the core regulatory pathway RP11-328K4.1-hsa-miR-27a-3p-PROS1, which is related to ICC, for further validation by molecular biology assays. GO analysis o ...[more]

PMID: 31956102

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Project description:BackgroundInflammation plays a critical role in tumor development. Inflammatory cell infiltration and inflammatory mediator synthesis cause changes in the tumor microenvironment (TME) in several cancers, especially in intrahepatic cholangiocellular carcinoma (ICC). However, methods to ascertain the inflammatory state of patients using reliable biomarkers are still being explored.MethodWe retrieved the RNA sequencing and somatic mutation analyses results and the clinical characteristics of 244 patients with ICC from published studies. We performed consensus clustering to identify the molecular subtypes associated with inflammation. We compared the prognostic patterns, clinical characteristics, somatic mutation profiles, and immune cell infiltration patterns across inflammatory subtypes. We performed quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) to confirm gene expression. We performed logistic regression analyses to construct a nomogram predicting the inflammatory status of patients with ICC.ResultsOur results confirmed that ICC can be categorized into an inflammation-high subtype (IHS) and an inflammation-low subtype (ILS). Patients from each group had distinct prognosis, clinical characteristics, and TME composition. Patients with ICC in the IHS group showed poorer prognosis owing to the immunosuppressive microenvironment and high frequency of KRAS and TP53 mutations. Cancer-associated fibroblast (CAF)-derived COLEC11 reduced myeloid inflammatory cell infiltration and attenuated inflammatory responses. The results of qRT-PCR and IHC experiments confirmed that COLEC11 expression levels were significantly reduced in tumor tissues compared to those in paracancerous tissues. Patients with ICC in the IHS group were more likely to respond to treatment with immune checkpoint inhibitors (ICIs) owing to their higher tumor mutational burden (TMB) scores, tumor neoantigen burden (TNB) scores, neoantigen counts, and immune checkpoint expression levels. Finally, we developed a nomogram to effectively predict the inflammatory status of patients with ICC based on their clinical characteristics and inflammatory gene expression levels. We evaluated the calibration, discrimination potential, and clinical utility of the nomogram.ConclusionThe inflammatory response in IHS is primarily induced by myeloid cells. COLEC11 can reduce the infiltration level of this group of cells, and myeloid inflammatory cells may be a novel target for ICC treatment. We developed a novel nomogram that could effectively predict the inflammatory state of patients with ICC, which will be useful for guiding individualized treatment plans.

Project description:Autism spectrum disorder (ASD) is a complex disorder of neurodevelopment, the function of long noncoding RNA (lncRNA) in ASD remains essentially unknown. In the present study, gene networks were used to explore the ASD disease mechanisms integrating multiple data types (for example, RNA expression, whole-exome sequencing signals, weighted gene co-expression network analysis, and protein-protein interaction) and datasets (five human postmortem datasets). A total of 388 lncRNAs and five co-expression modules were found to be altered in ASD. The downregulated co-expression M4 module was significantly correlated with ASD, enriched with autism susceptibility genes and synaptic signaling. Integrating lncRNAs from the M4 module and microRNA (miRNA) dysregulation data from the literature identified competing endogenous RNA (ceRNA) network. We identified the downregulated mRNAs that interact with miRNAs by the miRTarBase, miRDB, and TargetScan databases. Our analysis reveals that MIR600HG was downregulated in multiple brain tissue datasets and was closely associated with 9 autism-susceptible miRNAs in the ceRNA network. MIR600HG and target mRNAs (EPHA4, MOAP1, MAP3K9, STXBP1, PRKCE, and SCAMP5) were downregulated in the peripheral blood by quantitative reverse transcription polymerase chain reaction analysis (false discovery rate <0.05). Subsequently, we assessed the role of lncRNA dysregulation in altered mRNA levels. Experimental verification showed that some synapse-associated mRNAs were downregulated after the MIR600HG knockdown. BrainSpan project showed that the expression patterns of MIR600HG (primate-specific lncRNA) and synapse-associated mRNA were similar in different human brain regions and at different stages of development. A combination of support vector machine and random forest machine learning algorithms retrieved the marker gene for ASD in the ceRNA network, and the area under the curve of the diagnostic nomogram was 0.851. In conclusion, dysregulation of MIR600HG, a novel specific lncRNA associated with ASD, is responsible for the ASD-associated miRNA-mRNA axes, thereby potentially regulating synaptogenesis.

Dataset Information

CeRNA regulatory network-based analysis to study the roles of noncoding RNAs in the pathogenesis of intrahepatic cholangiocellular carcinoma.

Publications

CeRNA regulatory network-based analysis to study the roles of noncoding RNAs in the pathogenesis of intrahepatic cholangiocellular carcinoma.

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