Abstract
Background: Significant developments have been made in breast cancer diagnosis and treatment, yet the prognosis remains unsatisfactory. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play pivotal roles in the development and progression of human tumors. However, the regulatory mechanisms and clinical significance of most lncRNAs in breast cancer remain poorly understood.Methods: The lncRNA, miRNA, and mRNA expression profiles were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. A lncRNA-miRNA-mRNA regulatory network was constructed and visualized using Cytoscape. The protein-protein interaction (PPI) network was constructed using the STRING database and hub genes were extracted using the cytoHubba plugin. Gene Ontology and Kyoto Encyclopedia of Gene and Genomes analyses identified the functions and signaling pathways associated with these differentially expressed mRNAs (DEmRNAs). Expression of the key lncRNA and the relationship with prognosis of patients with breast cancer were evaluated.Results: Six differentially expressed lncRNAs (DElncRNAs), 29 differentially expressed miRNAs (DEmiRNAs), and 253 DEmRNAs were selected to construct the regulatory network. A PPI network was established and seven hub genes were identified. A lncRNA-miRNA-hub gene regulatory sub-network was established containing two DElncRNAs, five DEmiRNAs, and seven DEmRNAs. Hub genes were associated with breast cancer onset and progression. The upregulated DGUOK-AS1 was identified as the key lncRNA in breast cancer based on the competing endogenous RNA network. High DGUOK-AS1 expression was associated with adverse prognosis in patients with breast cancer and a prognostic nomogram built on Grade, LN status, and DGUOK-AS1 expression shows significant prognostic value.Conclusions: Our results reveal the significant roles of lncRNA/miRNA/mRNA regulatory networks in breast cancer and identified a novel prognosis predictor and promising therapeutic target for patients with breast cancer.
Highlights
Worldwide, breast cancer (BC) has a high level of morbidity
Using Cox and Lasso analyses, we found that high Deoxyguanosine kinase (DGUOK)-AS1 expression level was correlated with poor prognosis in patients with BC
We took the intersection of DElncRNAs of the three datasets, identifying three commonly upregulated Long non-coding RNAs (lncRNAs) and 10 commonly downregulated lncRNAs (Figure 2B, Table S3)
Summary
Breast cancer (BC) has a high level of morbidity. In 2018, BC was responsible for ∼2.1 million new cases and 627,000 deaths, making it the most frequently diagnosed malignancy and the second leading cause of cancer-related death among women [1]. There has been significant progress in personalizing treatment for BC, the 5-year overall survival remains relatively poor due to tumor heterogeneity. Elucidation of the molecular mechanisms underlying BC occurrence and progression is essential to enable the identification of novel therapeutic targets and potential molecular biomarkers for prognosis prediction. LncRNAs play essential roles in regulating various biological processes, including cell cycle control, drug resistance, and tumorigenesis [3]. Recent discoveries have indicated that several lncRNAs are frequently dysregulated in breast cancer and play a central role in tumorigenesis and metastasis by regulating gene expression [4, 5], indicating their diagnostic and prognostic value. Significant developments have been made in breast cancer diagnosis and treatment, yet the prognosis remains unsatisfactory. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play pivotal roles in the development and progression of human tumors. The regulatory mechanisms and clinical significance of most lncRNAs in breast cancer remain poorly understood
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