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Characterization of BRCA1/2-Directed ceRNA Network Identifies a Novel Three-lncRNA Signature to Predict Prognosis and Chemo-Response in Ovarian Cancer Patients With Wild-Type BRCA1/2.

ABSTRACT: Long non-coding RNAs (lncRNAs) have been reported to interact with BRCA1/2 to regulate homologous recombination (HR) by diverse mechanisms in ovarian cancers (OvCa). However, genome-wide screening of BRCA1/2-related lncRNAs and their clinical significance is still unexplored. In this study, we constructed a global BRCA1/2-directed lncRNA-associated ceRNA network by integrating paired lncRNA expression profiles, miRNA expression profiles, and BRCA1/2 expression profiles in BRCA1/2 wild-type patients and identified 111 BRCA1/2-related lncRNAs. Using the stepwise regression and Cox regression analysis, we developed a BRCA1/2-directed lncRNA signature (BRCALncSig), composing of three lncRNAs (LINC01619, DLX6-AS1, and AC004943.2) from the list of 111 BRCA1/2-related lncRNAs, which was an independent prognostic factor and was able to classify the patients into high- and low-risk groups with significantly different survival in the training dataset (HR = 2.73, 95 CI 1.65-4.51, p < 0.001). The prognostic performance of the BRCALncSig was further validated in the testing dataset (HR = 1.9, 95 CI 1.21-2.99, p = 0.005) and entire TCGA dataset (HR = 2.17, 95 CI 1.56-3.01, p < 0.001). Furthermore, the BRCALncSig is associated with chemo-response and was also capable of discriminating nonequivalent outcomes for patients achieving complete response (CR) (log-rank p = 0.003). Functional analyses suggested that mRNAs co-expressed with the BRCALncSig were enriched in cancer-related or cell proliferation-related biological processes and pathways. In summary, our study highlighted the clinical implication of BRCA1/2-directed lncRNAs in the prognosis and treatment response of BRCA1/2 wild-type patients.

SUBMITTER: Zhang M

PROVIDER: S-EPMC7403448 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Characterization of BRCA1/2-Directed ceRNA Network Identifies a Novel Three-lncRNA Signature to Predict Prognosis and Chemo-Response in Ovarian Cancer Patients With Wild-Type BRCA1/2.

Zhang Meiling M Wang Guangyou G Zhu Yuanyuan Y Wu Di D

Frontiers in cell and developmental biology 20200729

Long non-coding RNAs (lncRNAs) have been reported to interact with BRCA1/2 to regulate homologous recombination (HR) by diverse mechanisms in ovarian cancers (OvCa). However, genome-wide screening of BRCA1/2-related lncRNAs and their clinical significance is still unexplored. In this study, we constructed a global BRCA1/2-directed lncRNA-associated ceRNA network by integrating paired lncRNA expression profiles, miRNA expression profiles, and BRCA1/2 expression profiles in BRCA1/2 wild-type patie ...[more]

PMID: 32850807

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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.

Dataset Information

Characterization of BRCA1/2-Directed ceRNA Network Identifies a Novel Three-lncRNA Signature to Predict Prognosis and Chemo-Response in Ovarian Cancer Patients With Wild-Type BRCA1/2.

Publications

Characterization of BRCA1/2-Directed ceRNA Network Identifies a Novel Three-lncRNA Signature to Predict Prognosis and Chemo-Response in Ovarian Cancer Patients With Wild-Type BRCA1/2.

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