Oncogenic long noncoding RNA landscape in breast cancer

Shouping Xu,Da Pang,Yanyan Ping,Dejia Kong,Qianlin Chen

doi:10.1186/s12943-017-0696-6

Abstract

BackgroundFew long noncoding RNAs (lncRNAs) that act as oncogenic genes in breast cancer have been identified.MethodsOncogenic lncRNAs associated with tumourigenesis and worse survival outcomes were examined and validated in Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), respectively. Then, the potential biological functions and expression regulation of these lncRNAs were studied via bioinformatics and genome data analysis. Moreover, progressive breast cancer subtype-specific lncRNAs were investigated via high-throughput sequencing in our cohort and TCGA validation. To elucidate the mechanisms of the regulation of these lncRNAs, genomic alterations from the TCGA, Broad, Sanger and BCCRC data, as well as epigenetic modifications from GEO data, were then applied and examined to meet this objective. Finally, cell proliferation assays, flow cytometry analyses and TUNEL assays were applied to validate the oncogenic roles of these lncRNAs in vitro.ResultsA cluster of oncogenic lncRNAs that was upregulated in breast cancer tissue and was associated with worse survival outcomes was identified. These oncogenic lncRNAs are involved in regulating immune system activation and the TGF-beta and Jak-STAT signalling pathways. Moreover, TINCR, LINC00511, and PPP1R26-AS1 were identified as subtype-specific lncRNAs associated with HER-2, triple-negative and luminal B subtypes of breast cancer, respectively. The up-regulation of these oncogenic lncRNAs is mainly caused by gene amplification in the genome in breast cancer and other solid tumours. Finally, the knockdown of TINCR, DSCAM-AS1 or HOTAIR inhibited breast cancer cell proliferation, increased apoptosis and inhibited cell cycle progression in vitro.ConclusionsThese findings enhance the landscape of known oncogenic lncRNAs in breast cancer and provide insights into their roles. This understanding may potentially aid in the comprehensive management of breast cancer.

Highlights

Few long noncoding RNAs that act as oncogenic genes in breast cancer have been identified
In cohort I (GSE21653 and GSE31448), 137 long noncoding RNAs (lncRNAs) and 8914 coding genes showed significantly aberrant expression between breast cancer and normal tissue (P < 0.05); in cohort II (GSE10810, GSE29431, GSE23177, GSE42568, and GSE48391), 164 lncRNAs and 9685 coding genes were differentially expressed in breast cancer and normal tissues (P < 0.05) (Fig. 1a, b and Additional file 2: Table S2 and Additional file 3: Table S3)
Oncogenic lncRNAs are correlated with worse survival outcomes we investigated the relationship between breast cancer prognosis and the 30 aberrant upregulated lncRNAs obtained via in silico analysis from cohorts I & II

Summary

Introduction

Few long noncoding RNAs (lncRNAs) that act as oncogenic genes in breast cancer have been identified. The molecular mechanisms of tumourigenesis are still unclear in breast cancer. Identifying new genes related to tumourigenesis and patient prognosis, as well as elucidating the molecular mechanisms underlying these oncogenic processes, are urgently required. It is certified that less than 2% of the genome encodes proteins, but at least 75% are transcribed into noncoding RNAs [3]. Long noncoding RNAs (lncRNAs) are defined as transcripts that are longer than 200 nucleotides and have no protein-coding capacity [4]. LncRNAs share common features with mRNAs: many of them are transcribed by RNA polymerase II and undergo 5′-capping, polyadenylation and splicing [3]. LncRNAs have several distinct features that distinguish them from protein-coding mRNAs

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Conclusion