Abstract
BackgroundTriple-negative breast cancer (TNBC) is a type of highly invasive breast cancer with poor prognosis. Recently, massive data reveal that long non-coding RNAs (lncRNAs) play important roles in cancer progress. Recently, although the role of lncRNAs in breast cancer has been well documented, few focused on TNBC. In this study, we aimed to systematically identify functional lncRNAs and to explore its molecular mechanism on TNBC progress.MethodsThe recurrence of lncRNAs and their target genes were validated with TNBC biopsies and cell lines. Total one hundred and thirteen TNBC biopsies, including nineteen patient-matched samples, were collected. The profile of TNBC-related lncRNAs and their target genes were characterized by RNA sequencing (RNA-seq) and bioinformatic analysis. Tumor specific lncRNAs, which also showed biological function correlated with TNBC, were identified as potential candidates; and the target genes, which regulated by the identified lncRNAs, were predicted by the analysis of expression correlation and chromosome colocalization. Cross bioinformatic validation was performed with TNBC independent datasets from the cancer genome atlas (TCGA). The biological functions and molecular mechanism were investigated in TNBC model cell lines by cell colony forming assay, flow cytometry assay, western-blot, RNA Fluorescence in situ Hybridization assay (RNA FISH) and chromatin immunoprecipitation-qPCR (ChIP-qPCR).ResultsAbundant Lnc-BTG3-7:1, which targets gene C21ORF91, was specifically observed in TNBC biopsies and cell lines. Knockdown of Lnc-BTG3-7:1 or C21ORF91 strongly inhibited cell proliferation, promoted cell apoptosis and cell cycle G1-arrested. Meanwhile, investigation of molecular mechanism indicated that Lnc-BTG3-7:1, cooperated with transcription factor JUND, cis-regulated the transcription of C21ORF91 gene, and down-regulation of Lnc-BTG3-7:1/C21ORF91 suppressed GRB2-RAS-RAF-MEK-ERK and GRB2-PI3K-AKT-GSK3β-β-catenin pathways.ConclusionsIn this study, we identified a TNBC specific lncRNA Lnc-BTG3-7:1, which sustained tumor progress. Up-regulation of Lnc-BTG3-7:1 promoted the transcription of oncogene C21ORF91 and activated PI3K-AKT-GSK3β-β-catenin and MAPK pathways. Taken together, our results not only identified a biomarker for diagnosis but also provided a potential therapeutic target against TNBC.
Highlights
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is characterized by poor survival (Shah et al, 2012; Johnson et al, 2020), occurring from younger age and being prone to distant metastasis
48,551 (83.47%) were identified as known long non-coding RNAs (lncRNAs), and 9,612 novel lncRNAs were detected in TNBC tissues
To investigate the key lncRNAs involved in TNBC progress, the expression profiles of lncRNAs between tumor and normal tissues were compared in order to detect the differentially expressed lncRNAs (DE-lncRNAs)
Summary
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is characterized by poor survival (Shah et al, 2012; Johnson et al, 2020), occurring from younger age and being prone to distant metastasis. It is kind of a heterogeneous disease with complex genetic background (Network, 2012), which represents different prognosis and responds to chemotherapies (Masuda et al, 2013; Burstein et al, 2015). We aimed to systematically identify functional lncRNAs and to explore its molecular mechanism on TNBC progress
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