Dataset Information

Integrative Analysis of the Doxorubicin-Associated LncRNA-mRNA Network Identifies Chemoresistance-Associated lnc-TRDMT1-5 as a Biomarker of Breast Cancer Progression.

ABSTRACT: Increasing evidence has revealed close relationships between long non-coding RNAs (lncRNAs) and chemoresistance in multiple types of tumors; however, functional lncRNAs in breast cancer (BC) have not been completely identified. In this study, we aimed to identify novel lncRNAs that might play critical roles in doxorubicn resistance, which could reveal potential biomarkers of BC. Using a BC dataset (GSE81971), we identified 452 lncRNAs that were upregulated and 659 that were downregulated; furthermore, there were 1896 differentially expressed mRNAs, of which 1137 were upregulated and 758 were downregulated in MCF-7/ADR cells compared with the expression in MCF-7 cells. We constructed an lncRNA-mRNA network by integrating probe reannotation and regulatory interactions. To elucidate the key lncRNAs in BC, we further analyzed dysregulated lncRNA-mRNA crosstalk, and six candidate lncRNAs (lnc-TRDMT1-5, ZNF667-AS1, lnc-MPPE1-13, DSCAM-AS1:5, DSCAM-AS1:2, and lnc-CFI-3) were identified. Notably, the expression level of lnc-TRDMT1-5 was significantly upregulated in resistant cells compared with sensitive cells, and its levels were increased in BC tissues compared with adjacent tissues. Levels were positively associated with estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) expression levels. High expression of lnc-TRDMT1-5 predicted poor prognosis in ER-positve and HER2-positive BC patients, especially in patients with chemoresistance. Bioinformatic and functional analysis revealed that lnc-TRDMT1-5 was involved in many crucial pathways in cancer, such as the PI3K/AKT and Wnt signaling pathways. Subcellular localization predicted that lnc-TRDMT1-5 was located in the cytoplasm, and the lncRNA-miRNA-mRNA network showed that lnc-TRDMT1-5 might serve as a regulator in BC. Here, our results demonstrated a dysregulated lncRNA-mRNA network that might provide new treatment strategies for chemoresistant BC, and the results identified a new lncRNA, lnc-TRDMT1-5, with oncogenic and prognostic functions in human BC.

SUBMITTER: Chen Q

PROVIDER: S-EPMC7272716 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Integrative Analysis of the Doxorubicin-Associated LncRNA-mRNA Network Identifies Chemoresistance-Associated lnc-TRDMT1-5 as a Biomarker of Breast Cancer Progression.

Chen Qi Q Yang Hui H Zhu Xiaolan X Xiong Shangwan S Chi Huamao H Xu Wenlin W

Frontiers in genetics 20200529

Increasing evidence has revealed close relationships between long non-coding RNAs (lncRNAs) and chemoresistance in multiple types of tumors; however, functional lncRNAs in breast cancer (BC) have not been completely identified. In this study, we aimed to identify novel lncRNAs that might play critical roles in doxorubicn resistance, which could reveal potential biomarkers of BC. Using a BC dataset (GSE81971), we identified 452 lncRNAs that were upregulated and 659 that were downregulated; furthe ...[more]

PMID: 32547604

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Project description:BackgroundIncreasing evidence has underscored the role of long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) in the development and progression of tumors. Nevertheless, lncRNA biomarkers in lncRNA-related ceRNA network that can predict the prognosis of breast cancer (BC) are still lacking. The aim of our study was to identify potential lncRNA signatures capable of predicting overall survival (OS) of BC patients.MethodsThe RNA sequencing data and clinical characteristics of BC patients were obtained from the Cancer Genome Atlas database, and differentially expressed lncRNA (DElncRNAs), DEmRNAs, and DEmiRNAs were then identified between BC and normal breast tissue samples. Subsequently, the lncRNA-miRNA-mRNA ceRNA network of BC was established, and the gene oncology enrichment analyses for the DEmRNAs interacting with lncRNAs in the ceRNA network was implemented. Using univariate and multivariate Cox regression analyses, a four-lncRNA signature was developed and used for predicting the survival in BC patients. We applied receiver operating characteristic analysis to assess the performance of our model.ResultsA total of 1061 DElncRNAs, 2150 DEmRNAs, and 82 DEmiRNAs were identified between BC and normal breast tissue samples. A lncRNA-miRNA-mRNA ceRNA network of BC was established, which comprised of 8 DEmiRNAs, 48 DElncRNAs, and 10 DEmRNAs. Further gene oncology enrichment analyses revealed that the DEmRNAs interacting with lncRNAs in the ceRNA network participated in cell leading edge, protease binding, alpha-catenin binding, gamma-catenin binding, and adenylate cyclase binding. A univariate regression analysis of the DElncRNAs revealed 7 lncRNAs (ADAMTS9-AS1, AC061992.1, LINC00536, HOTAIR, AL391421.1, TLR8-AS1 and LINC00491) that were associated with OS of BC patients. A multivariate Cox regression analysis demonstrated that 4 of those lncRNAs (ADAMTS9-AS1, LINC00536, AL391421.1 and LINC00491) had significant prognostic value, and their cumulative risk score indicated that this 4-lncRNA signature independently predicted OS in BC patients. Furthermore, the area under the curve of the 4-lncRNA signature associated with 3-year survival was 0.696.ConclusionsThe current study provides novel insights into the lncRNA-related ceRNA network in BC and the 4 lncRNA biomarkers may be independent prognostic signatures in predicting the survival of BC patients.

Project description:BackgroundGastric cancer (GC) is a malignant tumour that originates in the gastric mucosal epithelium and is associated with high mortality rates worldwide. Long noncoding RNAs (lncRNAs) have been identified to play an important role in the development of various tumours, including GC. Yet, lncRNA biomarkers in a competing endogenous RNA network (ceRNA network) that are used to predict survival prognosis remain lacking. The aim of this study was to construct a ceRNA network and identify the lncRNA signature as prognostic factors for survival prediction.MethodsThe lncRNAs with overall survival significance were used to construct the ceRNA network. Function enrichment, protein-protein interaction, and cluster analysis were performed for dysregulated mRNAs. Multivariate Cox proportional hazards regression was performed to screen the potential prognostic lncRNAs. RT-qPCR was used to measure the relative expression levels of lncRNAs in cell lines. CCK8 assay was used to assess the proliferation of GC cells transfected with sh-lncRNAs.ResultsDifferentially expressed genes were identified including 585 lncRNAs, 144 miRNAs, and 2794 mRNAs. The ceRNA network was constructed using 35 DElncRNAs associated with overall survival of GC patients. Functional analysis revealed that these dysregulated mRNAs were enriched in cancer-related pathways, including TGF-beta, Rap 1, calcium, and the cGMP-PKG signalling pathway. A multivariate Cox regression analysis and cumulative risk score suggested that two of those lncRNAs (LINC01644 and LINC01697) had significant prognostic value. Furthermore, the results indicate that LINC01644 and LINC01697 were upregulated in GC cells. Knockdown of LINC01644 or LINC01697 suppressed the proliferation of GC cells.ConclusionsThe authors identified 2-lncRNA signature in ceRNA regulatory network as prognostic biomarkers for the prediction of GC patient survival and revealed that silencing LINC01644 or LINC01697 inhibited the proliferation of GC cells.

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Project description:Chronic epididymitis (CE) refers to a long-lasting inflammatory condition of the epididymis, which is considered the most common site of intrascrotal inflammation and an important aetiological factor of male infertility. Recent studies demonstrate that small RNAs secreted from epididymal epithelium modulate embryo development and offspring phenotypes via sperm transmission, and the resulting modifications may lead to transgenerational inheritance. However, to date, the genome-wide analysis of small RNA together with the transcriptomic expression profiles of human epididymis and CE is still lacking. In this study, we facilitated next-generation sequencing and bioinformatics to comprehensively analyze the small RNA and mRNA in an integrative way and identified signatures associated with CE. Both of the small RNA and mRNA expression data demonstrated relatively larger molecular differences among the segmental region of the epididymides, including caput, corpus, and cauda, than that of the inflammatory conditions. By comparing the inflamed caputs to the controls, a total of 1727 genes (1220 upregulated and 507 downregulated; 42 most significant genes, adjusted P <0.05) and 34 miRNAs (23 upregulated and 11 downregulated) were identified as differentially expressed. In silico functional enrichment analysis showed their roles in regulating different biological activities, including leukocyte chemotaxis, extracellular milieu reconstruction, ion channel and transporter-related processes, and nervous system development. Integrative analysis of miRNA and mRNA identified a regulatory network consisting of 22 miRNAs and 31 genes (miRNA-mRNA) which are strong candidates for CE. In addition, analysis about other species of small RNA, including (miRNA), piwi-interacting RNA (piRNA), tRNA-derived small RNA (tsRNA), Y RNA, and rsRNA identified the distinct expression pattern of tsRNA in CE. In summary, our study performed small RNA and miRNA profiling and integrative analysis in human CE. The findings will help to understand the role of miRNA-mRNA in the pathogenesis of CE and provide molecular candidates for the development of potential biomarkers for human CE.

Dataset Information

Integrative Analysis of the Doxorubicin-Associated LncRNA-mRNA Network Identifies Chemoresistance-Associated lnc-TRDMT1-5 as a Biomarker of Breast Cancer Progression.

Publications

Integrative Analysis of the Doxorubicin-Associated LncRNA-mRNA Network Identifies Chemoresistance-Associated lnc-TRDMT1-5 as a Biomarker of Breast Cancer Progression.

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