Mitotically-Associated lncRNA (MANCR) Affects Genomic Stability and Cell Division in Aggressive Breast Cancer.
Mitotically-Associated lncRNA (MANCR) Affects Genomic Stability and Cell Division in Aggressive Breast Cancer.
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DOI：
10.1158/1541-7786.mcr-17-0548
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发表时间：
2018-04
期刊：
影响因子：
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通讯作者：
Lian JB
中科院分区：
文献类型：
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作者：
Tracy KM;Tye CE;Ghule PN;Malaby HLH;Stumpff J;Stein JL;Stein GS;Lian JB
侵袭性乳腺癌很难治疗，因为它对许多基于激素的疗法没有反应；因此，必须找到新颖的、有针对性的进展调节因子。长链非编码RNA（lncRNA）是乳腺癌的重要调节因子，具有作为治疗靶点的巨大潜力；然而，人们对大多数 lncRNA 如何在乳腺癌中发挥作用知之甚少。这项研究描述了一种新型 lncRNA，MANCR（有丝分裂相关长非编码 RNA；LINC00704），它在乳腺癌患者标本和细胞中表达上调。三阴性乳腺癌 (TNBC) 细胞中 MANCR 的缺失会显着降低细胞增殖和活力，同时 DNA 损伤也会增加。 MANCR 敲低后，基于 RNA 测序 (RNA-seq) 的转录组分析揭示了超过 2000 个转录本的表达存在显着差异，而基因集富集分析 (GSEA) 则识别了与细胞周期调控相关的多个类别的变化。此外，通过 RT-qPCR 和 RNA 原位杂交，MANCR 表达在有丝分裂细胞中最高。与细胞周期调节中的作用一致，MANCR耗尽的细胞有丝分裂指数较低，胞质分裂缺陷和细胞死亡的发生率较高。总而言之，这些数据揭示了新型 lncRNA MANCR 在侵袭性乳腺癌基因组稳定性中的作用，并将其确定为潜在的治疗靶点。新型 lncRNA MANCR (LINC00704) 在乳腺癌中表达上调，并且在功能上与细胞增殖、活力和基因组稳定性相关。
Aggressive breast cancer is difficult to treat as it is unresponsive to many hormone-based therapies; therefore, it is imperative to identify novel, targetable regulators of progression. Long non-coding RNAs (lncRNAs) are important regulators in breast cancer and have great potential as therapeutic targets; however, little is known about how the majority of lncRNAs function within breast cancer. This study, characterizes a novel lncRNA, MANCR (mitotically-associated long non-coding RNA; LINC00704), which is upregulated in breast cancer patient specimens and cells. Depletion of MANCR in triple-negative breast cancer (TNBC) cells significantly decreases cell proliferation and viability, with concomitant increases in DNA damage. Transcriptome analysis, based on RNA sequencing (RNA-seq), following MANCR knockdown reveals significant differences in the expression of >2000 transcripts, and gene set enrichment analysis (GSEA) identifies changes in multiple categories related to cell cycle regulation. Furthermore, MANCR expression is highest in mitotic cells by both RT-qPCR and RNA in situ hybridization. Consistent with a role in cell cycle regulation, MANCR-depleted cells have a lower mitotic index and higher incidences of defective cytokinesis and cell death. Taken together, these data reveal a role for the novel lncRNA, MANCR, in genomic stability of aggressive breast cancer, and identify it as a potential therapeutic target. The novel lncRNA, MANCR (LINC00704), is upregulated in breast cancer and is functionally linked with cell proliferation, viability, and genomic stability.