Dataset Information

Analysis of the lncRNA-miRNA-mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC.

ABSTRACT: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are widely used for patients with EGFR-mutated lung cancer. Despite its initial therapeutic efficacy, most patients eventually develop drug resistance, which leads to a poor prognosis in lung cancer patients. Previous investigations have proved that non-coding RNAs including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) contribute to drug resistance by various biological functions, whereas how they regulate EGFR-TKI resistance remains unclear. In this study, we examined gene expression using the microarray technology on gefitinib-resistant NSCLC cells to obtain differentially expressed (DE) lncRNAs and mRNAs. A total of 45 DE-lncRNAs associated with overall survival and 1799 target DE-mRNAs were employed to construct a core lncRNA-miRNA-mRNA network to illustrate underlying molecular mechanisms of how EGFR-TKI resistance occurs in NSCLC. We found that target DE-mRNAs were mainly enriched in pathways involved in EGFR-TKI resistance, especially the target DE-mRNAs regulated by LINC01128 were significantly enriched in the PI3K/Akt signaling pathway, where the synergy of these target DE-mRNAs may play a key role in EGFR-TKI resistance. In addition, downregulated LINC01128, acting as a specific miRNA sponge, decreases PTEN via sponging miR-25-3p. Furthermore, signaling reactions caused by the downregulation of PTEN would activate the PI3K/Akt signaling pathway, which may lead to EGFR-TKI resistance. In addition, a survival analysis indicated the low expression of LINC01128, and PTEN is closely related to poor prognosis in lung adenocarcinoma (LUAD). Therefore, the LINC01128/miR-25-3p/PTEN axis may promote EGFR-TKI resistance via the PI3K/Akt signaling pathway, which provides new insights into the underlying molecular mechanisms of drug resistance to EGFR-TKIs in NSCLC. In addition, our study sheds light on developing novel therapeutic approaches to overcome EGFR-TKI resistance in NSCLC.

SUBMITTER: Ding D

PROVIDER: S-EPMC9099042 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Analysis of the lncRNA-miRNA-mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC.

Ding Dandan D Zhang Jufeng J Luo Zhiming Z Wu Huazhen H Lin Zexiao Z Liang Weicheng W Xue Xingyang X

Frontiers in genetics 20220429

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are widely used for patients with EGFR-mutated lung cancer. Despite its initial therapeutic efficacy, most patients eventually develop drug resistance, which leads to a poor prognosis in lung cancer patients. Previous investigations have proved that non-coding RNAs including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) contribute to drug resistance by various biological functions, whereas ...[more]

PMID: 35571024

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Project description:Long non-coding RNAs (lncRNAs) are ncRNA transcripts >200 nucleotides that are important genetic regulators. LncRNAs can directly regulate mRNA through a lncRNA-mRNA regulatory mode and can also regulate mRNA through competitive binding to micro (mi)RNA, which is generally known as the competitive endogenous RNA (ceRNA) network. The present study evaluated the functional roles and regulatory networks of lncRNAs in chronic glomerulonephritis (CGN). The proliferative ability of mouse glomerular mesangial cells (GMCs) induced by different concentrations of lipopolysaccharide (LPS) was assessed using the Cell Counting Kit-8 assay, and RNA sequencing (RNA-seq) was performed to identify differentially expressed lncRNAs in LPS-induced GMCs. Based on the sequencing results, six lncRNAs were selected for validation using reverse transcription-quantitative PCR (RT-qPCR). Furthermore, the lncRNA-mRNA regulatory network and the lncRNA-miRNA-mRNA ceRNA network were constructed to assess the role and mechanism of CGN-related lncRNAs. To elucidate the biological functions of lncRNAs, Gene Ontology (GO) biological process term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on all mRNAs involved in the lncRNA-mRNA regulatory network and in the ceRNA network. A total of 1,532 differentially expressed lncRNAs, including 594 upregulated lncRNAs and 938 downregulated lncRNAs, were identified using RNA-seq. The results of RT-qPCR validation were consistent with RNA-seq results. An lncRNA-mRNA regulatory network, including 236 lncRNAs and 556 mRNAs, and a ceRNA network, including 6 lncRNAs, 18 miRNAs and 419 mRNAs, were successfully constructed. The GO biological process term enrichment and KEGG pathway enrichment analyses demonstrated that those lncRNAs were often related to inflammatory response and substance metabolism. The present study identified key CGN-related lncRNAs in LPS-induced GMCs, and further demonstrated a global view of the lncRNA-mRNA regulatory network and ceRNA network involved in CGN. These results offered novel insights into the roles of lncRNAs in the pathogenesis of CGN and identified potential diagnostic biomarkers.

Project description:BackgroundLong non-coding RNAs (lncRNAs) play critical roles in various biological processes in plants. Extensive studies utilizing high-throughput RNA sequencing have revealed that many lncRNAs are involved in plant disease resistance. Oryza sativa RNase P protein 30 (OsRpp30) has been identified as a positive regulator of rice immunity against fungal and bacterial pathogens. Nevertheless, the specific functions of lncRNAs in relation to OsRpp30-mediated disease resistance in rice remain elusive.ResultsWe conducted a comprehensive analysis of lncRNAs, miRNAs, and mRNAs expression patterns in wild type (WT), OsRpp30 overexpression (OsRpp30-OE), and OsRpp30 knockout (OsRpp30-KO) rice plants. In total, we identified 91 differentially expressed lncRNAs (DElncRNAs), 1671 differentially expressed mRNAs (DEmRNAs), and 41 differentially expressed miRNAs (DEmiRNAs) across the different rice lines. To gain further insights, we investigated the interaction between DElncRNAs and DEmRNAs, leading to the discovery of 10 trans- and 27 cis-targeting pairs specific to the OsRpp30-OE and OsRpp30-KO samples. In addition, we constructed a competing endogenous RNA (ceRNA) network comprising differentially expressed lncRNAs, miRNAs, and mRNAs to elucidate their intricate interplay in rice disease resistance. The ceRNA network analysis uncovered a set of gene targets regulated by lncRNAs and miRNAs, which were found to be involved in pathogen recognition, hormone pathways, transcription factor activation, and other biological processes related to plant immunity.ConclusionsOur study provides a comprehensive expression profiling of lncRNAs, miRNAs, and mRNAs in a collection of defense mutants in rice. To decipher the putative functional significance of lncRNAs, we constructed trans- and cis-targeting networks involving differentially expressed lncRNAs and mRNAs, as well as a ceRNA network incorporating differentially expressed lncRNAs, miRNAs, and mRNAs. Together, the findings from this study provide compelling evidence supporting the pivotal roles of lncRNAs in OsRpp30-mediated disease resistance in rice.

Project description:BackgroundLong non-coding RNAs (lncRNAs) are essential regulators for various human cancers. However, these lncRNAs need to be further classified for cancer. In the present study, we identified novel competing endogenous RNA (ceRNA) network for bladder cancer (BC) and explored the gene functions of the ceRNA regulatory network.MethodsDifferential gene expression analysis were performed on The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) datasets to identify differentially expressed messenger RNAs (mRNAs), lncRNAs, and microRNAs (miRNAs). Based on the competing endogenous RNA (ceRNA) hypothesis, a lncRNA-miRNA-mRNA network was constructed using the StarBase database and visualization by Cytoscape software. Functional enrichment analyses of Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed via R package ClusterProfiler. The protein-protein interaction network was constructed by STRING database and visualization by Cytoscape. Finally, we used CIBERSORT and the TIMER database to analyze the immune infiltrations for BC.ResultsThe regulatory network was constructed via TCGA BLCA cohort. The differential expressions of lncRNA, miRNA, and mRNA were 186, 200, and 2,661, respectively. There were 106 lncRNA, miRNA, and mRNA included in the ceRNA network. In this network, Calcium Voltage-gated Channel Auxiliary Subunit Alpha2delta1 (CACNA2D1, P<0.001), domain containing engulfment adaptor1 (GULP1, P=0.001), latent transforming growth factor beta binding protein 1 (LTBP1, P=0.006), myosin light chain kinase (MYLK, P=0.001), serpin family E member 2 (SERPINE2, P=0.002), spectrin beta non-erythrocytic 2 (SPTBN2, P=0.047), and hsa-miR-590-3p (P<0.001) significantly affected the prognosis of BC patients. Functional enrichment analyses showed that the biological functions included negative regulation of protein phosphorylation, cell morphogenesis, and sensory organ morphogenesis. Important cancer pathways of KEGG included parathyroid hormone synthesis secretion action, the notch signaling pathway, MAPK signaling pathway, the Rap1 signaling pathway, signaling pathways regulating the pluripotency of stem cells, and the transforming growth factor-β signaling pathway. Our findings demonstrated that the ceRNA network has important biological functions and a significant influence on the prognosis of BC.ConclusionsThe lncRNA-miRNA-mRNA network constructed in the present study could provide useful insight into the underlying tumorigenesis of BC, and can determine new molecular biomarkers for the diagnosis and therapeutical treatment of BC.

Project description:BackgroundOsteosarcoma is a common malignant primary bone tumor in adolescents and children. Numerous studies have shown that circRNAs were involved in the proliferation and invasion of various tumors. However, the role of circRNAs in osteosarcoma remains unclear. Here, we aimed to explore the regulatory network among circRNA-miRNA-mRNA in osteosarcoma.MethodsThe circRNA (GSE140256), microRNA (GSE28423), and mRNA (GSE99671) expression profiles of osteosarcoma were collected from the Gene Expression Omnibus (GEO) database. Differentially expressed circRNAs, miRNAs and mRNAs were identified. CircRNA-miRNA interactions and miRNA-mRNA interactions were determined by Circular RNA Interactome (CircInteractome) database and microRNA Data Integration Portal (mirDIP) database, respectively. Then, we constructed a regulatory network. Function enrichment analysis of miRNA and mRNA was performed by DIANA-miRPath v3.0 and Metascape database, respectively. mRNAs with significant prognostic value were identified based on expression profiles from The Cancer Genome Atlas (TCGA) database, and we constructed a subnetwork for them. To make the most of the network, we used the CLUE database to predict potential drugs for the treatment of osteosarcoma based on mRNA expression in the network. And we used the STITCH database to analyze and validate the interactions among these drugs and mRNAs, and to further screen for potential drugs.ResultsA total of 9 circRNAs, 19 miRNAs, 67 mRNAs, 54 pairs of circRNA-miRNA interactions and 110 pairs of miRNA-mRNA interactions were identified. A circRNA-miRNA-mRNA network was constructed. Function enrichment analysis indicated that these miRNAs and mRNAs in the network were involved in the process of tumorigenesis and immune response. Among these mRNAs, STC2 and RASGRP2 with significantly prognostic value were identified, and we constructed a subnetwork for them. Based on mRNA expression in the network, three potential drugs, quinacridine, thalidomide and zonisamide, were screened for the treatment of osteosarcoma. Among them, quinacridine and thalidomide have been proved to have anti-tumor effects in previous studies, while zonisamide has not been reported. And a corresponding drug-protein interaction network was constructed.ConclusionOverall, we constructed a circRNA-miRNA-mRNA regulatory network to investigate the possible mechanism in osteosarcoma, and predicted that quinacridine, thalidomide and zonisamide could be potential drugs for the treatment of osteosarcoma.

Dataset Information

Analysis of the lncRNA-miRNA-mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC.

Publications

Analysis of the lncRNA-miRNA-mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC.

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