LncRNA CARMN overexpression promotes prognosis and chemosensitivity of triple negative breast cancer via acting as miR143-3p host gene and inhibiting DNA replication.
LncRNA CARMN overexpression promotes prognosis and chemosensitivity of triple negative breast cancer via acting as miR143-3p host gene and inhibiting DNA replication.
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LncRNA CARMN过表达通过作为miR143-3p宿主基因，抑制DNA复制，促进三阴性乳腺癌的预后和化疗敏感性。
DOI：
10.1186/s13046-021-02015-4
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发表时间：
2021-06-23
期刊：
影响因子：
--
通讯作者：
Lu J
中科院分区：
文献类型：
--
作者：
Sheng X;Dai H;Du Y;Peng J;Sha R;Yang F;Zhou L;Lin Y;Xu S;Wu Y;Yin W;Lu J
三阴性乳腺癌（Triple Negative Breast Cancer，TNBC）是一种预后差、缺乏有效治疗靶点的乳腺癌亚型。在这里，我们通过生物信息学分析筛选差异表达的lncRNA，并将CARMN鉴定为在TNBC中表达最低的下调的lncRNA。我们的目的是确定CARMN在TNBC中的潜在作用和分子机制。在乳腺癌队列中探索CARMN的预测价值。将具有CARMN过表达或CARMN沉默的TNBC细胞系用于体外和体内实验。进行CARMN过表达细胞的RNA-seq以探索CARMN的下游。CARMN在乳腺组织恶性转化的不同阶段下调。CARMN可预测乳腺癌顺铂新辅助化疗的良好预后和较高的有效率。建立了预测乳腺癌顺铂化疗反应的列线图。通过体外和体内研究，我们证实CARMN还可以抑制TNBC细胞的肿瘤发生并增强对顺铂的敏感性。RNA-seq和进一步的实验表明CARMN可以抑制DNA复制。MCM 5是一个重要的DNA复制起始因子，是CARMN过表达后DNA复制途径中下调最多的基因。我们证实CARMN可以从其外显子5产生miR 143 - 3 p，这是DROSHA和DICER依赖性的，导致结合和减少MCM 5。此外，抑制miR 143 - 3 p可以削弱CARMN在抑制肿瘤发生和促进化疗敏感性方面的功能。我们的结果表明lncRNA CARMN是TNBC中更好预后和增强顺铂敏感性的预测生物标志物。CARMN是miR 143 - 3 p的宿主基因，其下调MCM 5，导致DNA复制抑制。在线版本包含补充材料，可通过10.1186/s13046-021-02015-4获得。
Triple negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis and lack of effective treatment target. Here we screened differentially expressed lncRNAs through bioinformatics analysis and identified CARMN as a downregulated lncRNA which is lowest expressed in TNBC. We aimed to identify the potential role and molecular mechanisms of CARMN in TNBC. Predictive value of CARMN was explored in breast cancer cohorts. TNBC cell lines with CARMN overexpression or CARMN silence and were used for in vitro and in vivo experiments. RNA-seq of CARMN overexpressed cells was performed for exploring downstream of CARMN. CARMN is downregulated at different phase of malignant transformation of breast tissue. CARMN can predict both better prognosis and higher response rate of cisplatin-based neoadjuvant chemotherapy in breast cancer. A nomogram is built to predict cisplatin-based chemotherapy response in breast cancer. Through in vitro and in vivo studies, we confirmed CARMN can also inhibit tumorigenesis and enhance sensitivity to cisplatin in TNBC cells. RNA-seq and further experiments revealed CARMN can inhibit DNA replication. MCM5, an important DNA replication initiation factor, is the most downregulated gene in DNA replication pathway following CARMN overexpression. We confirmed CARMN can produce miR143-3p from its exon5 which is DROSHA and DICER dependent, resulting binding and decrease of MCM5. Moreover, suppressing miR143-3p can weaken function of CARMN in suppressing tumorigenesis and promoting chemosensitivity. Our results indicated lncRNA CARMN is a predictive biomarker of better prognosis and enhanced cisplatin sensitivity in TNBC. CARMN is the host gene of miR143-3p which downregulates MCM5, causing inhibited DNA replication. The online version contains supplementary material available at 10.1186/s13046-021-02015-4.
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