Long Non-coding RNA BTG3-7:1 and JUND Co-regulate C21ORF91 to Promote Triple-Negative Breast Cancer Progress.
Long Non-coding RNA BTG3-7:1 and JUND Co-regulate C21ORF91 to Promote Triple-Negative Breast Cancer Progress.
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长链非编码RNA BTG3-7:1与JUND共同调控C21ORF91促进三阴性乳腺癌进展
DOI：
10.3389/fmolb.2020.605623
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发表时间：
2020
影响因子：
5
通讯作者：
Jing J
中科院分区：
文献类型：
--
作者：
Dan Z;Xiujing H;Ting L;Xiaorong Z;Hong Z;Jiqiao Y;Yanchu L;Jing J
研究背景三阴性乳腺癌（TNBC）是一种高度侵袭性、预后差的乳腺癌。近年来，大量数据表明，长链非编码RNA（lncRNA）在肿瘤发生、发展过程中起着重要作用。最近，虽然lncRNA在乳腺癌中的作用已经有了很好的记录，但很少有人关注TNBC。本研究旨在系统鉴定功能性lncRNA，并探讨其在TNBC进展中的分子机制。方法通过TNBC活检和细胞系验证lncRNA及其靶基因的复发。共收集了113份TNBC活检标本，包括19份患者匹配样本。通过RNA测序（RNA-seq）和生物信息学分析对TNBC相关lncRNA及其靶基因的谱进行了表征。通过表达相关性分析和染色体共定位分析，预测了肿瘤特异性lncRNA调控的靶基因。用来自癌症基因组图谱（TCGA）的TNBC独立数据集进行交叉生物信息学验证。采用细胞集落形成实验、流式细胞术、Western-blot、RNA荧光原位杂交（RNA FISH）和染色质免疫沉淀-qPCR（ChIP-qPCR）等方法，对TNBC模型细胞系的生物学功能和分子机制进行研究。结果在TNBC活检组织和细胞系中特异性地观察到丰富的靶向基因C21 ORF 91的Lnc-BTG 3 -7：1。Lnc-BTG 3 -7：1或C21 ORF 91基因的敲除可明显抑制细胞增殖，促进细胞凋亡，使细胞周期G1期阻滞。同时，分子机制研究表明，Lnc-BTG 3 -7：1与转录因子JUND协同作用，顺式调节C21 ORF 91基因的转录，下调Lnc-BTG 3 -7：1/C21 ORF 91可抑制GRB 2-RAS-RAF-MEK-ERK和GRB 2-PI 3 K-AKT-GSK 3 β-β-catenin通路。结论在这项研究中，我们鉴定了TNBC特异性lncRNA Lnc-BTG 3 -7：1，其维持肿瘤进展。Lnc-BTG 3 -7：1的上调可促进癌基因C21 ORF 91的转录，激活PI 3 K-AKT-GSK 3 β-β-catenin和MAPK通路。总之，我们的结果不仅确定了诊断的生物标志物，而且还提供了针对TNBC的潜在治疗靶点。
Background Triple-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. Methods The 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). Results Abundant 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. Conclusions In 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.
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影响因子：
21.3
作者：
Lin A;Li C;Xing Z;Hu Q;Liang K;Han L;Wang C;Hawke DH;Wang S;Zhang Y;Wei Y;Ma G;Park PK;Zhou J;Zhou Y;Hu Z;Zhou Y;Marks JR;Liang H;Hung MC;Lin C;Yang L
通讯作者：
Yang L
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
37.3
作者：
Augoff K;McCue B;Plow EF;Sossey-Alaoui K
通讯作者：
Sossey-Alaoui K
长非编码 RNA OIP5-AS1 通过在氧化应激下阻断 POLG 表达来抑制细胞凋亡和白内障形成
影响因子：
4.4
作者：
Jing R;Ma B;Qi T;Hu C;Liao C;Wen C;Shao Y;Pei C
通讯作者：
Pei C