Xu Shouping, Kong Dejia, Chen Qianlin, Ping Yanyan, Pang Da
Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Mol Cancer. 2017 Jul 24;16(1):129. doi: 10.1186/s12943-017-0696-6.
Few long noncoding RNAs (lncRNAs) that act as oncogenic genes in breast cancer have been identified.
Oncogenic 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.
A 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.
These 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.
在乳腺癌中作为致癌基因的长链非编码RNA（lncRNA）鲜有被鉴定出来。
分别在基因表达综合数据库（GEO）和癌症基因组图谱（TCGA）中检测并验证与肿瘤发生及较差生存结果相关的致癌lncRNA。然后，通过生物信息学和基因组数据分析研究这些lncRNA的潜在生物学功能和表达调控。此外，通过高通量测序在我们的队列中及TCGA验证中研究进展期乳腺癌亚型特异性lncRNA。为阐明这些lncRNA的调控机制，随后应用并检查了来自TCGA、布罗德研究所、桑格研究所和卑诗省癌症研究中心（BCCRC）数据的基因组改变以及来自GEO数据的表观遗传修饰以实现这一目标。最后，应用细胞增殖试验、流式细胞术分析和TUNEL试验在体外验证这些lncRNA的致癌作用。
鉴定出一组在乳腺癌组织中上调且与较差生存结果相关的致癌lncRNA。这些致癌lncRNA参与调节免疫系统激活以及TGF-β和Jak-STAT信号通路。此外，TINCR、LINC00511和PPP1R26-AS1分别被鉴定为与乳腺癌的HER-2、三阴性和管腔B亚型相关的亚型特异性lncRNA。这些致癌lncRNA的上调主要由乳腺癌和其他实体瘤基因组中的基因扩增引起。最后，敲低TINCR、DSCAM-AS1或HOTAIR可抑制乳腺癌细胞增殖，增加细胞凋亡并在体外抑制细胞周期进程。
这些发现拓展了乳腺癌中已知致癌lncRNA的格局，并为其作用提供了见解。这种认识可能有助于乳腺癌的综合管理。
