The β-catenin-LINC00183-miR-371b-5p-Smad2/LEF1 axis promotes adult T-cell lymphoblastic lymphoma progression and chemoresistance.
The β-catenin-LINC00183-miR-371b-5p-Smad2/LEF1 axis promotes adult T-cell lymphoblastic lymphoma progression and chemoresistance.
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β-连环蛋白-LINC00183-miR-371b-5p-Smad2/LEF1轴促进成人T细胞淋巴母细胞性淋巴瘤的进展和化疗耐药。
DOI：
10.1186/s13046-023-02670-9
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发表时间：
2023-04-28
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影响因子：
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高强度化疗方案常用于成人T细胞淋巴母细胞性淋巴瘤（T-LBL）患者。然而，由于耐药性的出现，缓解率仍然不令人满意。越来越多的证据表明，长链非编码RNA（lncRNA）参与肿瘤进展和化疗耐药性。在此，我们研究了lncRNA在T-LBL中的潜在作用。RNAseq用于筛选和鉴定与T-LBL进展和化学抗性相关的候选lncRNA。荧光素酶报告基因检测miR-371 b-5 p与Smad 2和LEF 1的3 'UTR的结合，以及TCF-4/LEF 1与LINC 00183启动子的结合。染色质免疫沉淀法分析LEF 1与LINC 00183启动子区之间的连接。RNA免疫沉淀法用于探索LINC 00183调节miR-371 b-5 p的机制。MTT法和流式细胞术检测T-LBL细胞凋亡。LINC 00183在中山大学肿瘤中心数据集和安徽医科大学第一附属医院数据集中的T-LBL进展和化疗耐药组织中上调。与LINC 00183低表达的患者相比，LINC 00183高表达与T-LBL患者较差的总生存期和无进展生存期相关。此外，miR-371 b-5 p被LINC 00183负调控。体内和体外试验表明，LINC 00183介导的T-LBL化疗耐药性依赖于miR-371 b-5 p表达。通过荧光素酶测定验证miR-371 b-5 p与Smad 2和LEF 1的直接结合。结果表明，TCF 4/LEF 1能够与LINC 00183启动子结合，并提高其转录水平。miR-371 b-5 p的下调导致Smad 2/LEF 1的表达增加，进而增加LINC 00183的表达。此外，磷酸化Smad 2促进β-catenin的核转位，LINC 00183下调由β-catenin和TGF-β1诱导的T-LBL细胞的化疗耐药性降低。我们揭示了β-catenin-LINC 00183-miR-371 b-5 p-Smad 2/LEF 1反馈环促进T-LBL进展和化疗耐药性，表明LINC 00183可能作为T-LBL的潜在治疗靶点。在线版本包含补充材料，可通过10.1186/s13046-023-02670-9获得。
High-intensity chemotherapy regimens are often used in adult T-cell lymphoblastic lymphoma (T-LBL) patients. Nevertheless, the response rate remains unsatisfactory due to emergence of chemoresistance. Growing evidence has shown that long non-coding RNAs (lncRNAs) are involved in tumor progression and chemoresistance. Herein, we investigated the potential role of lncRNAs in T-LBLs. RNAseq was used to screen and identify candidate lncRNAs associated with T-LBL progression and chemoresistance. Luciferase reporter assay was used to examine the binding of miR-371b-5p to the 3’UTR of Smad2 and LEF1, and the binding of TCF-4/LEF1 to the promoter of LINC00183. Chromatin immunoprecipitation assay was undertaken to analyze the connection between LEF1 and the LINC00183 promoter region. RNA immunoprecipitation assays were used to explore the mechanism whereby LINC00183 regulated miR-371b-5p. MTT and flow cytometry assays were used to measure apoptosis of T-LBL cells. LINC00183 was upregulated in T-LBL progression and chemoresistant tissues in both the Sun Yat-sen University Cancer Center dataset and the First Affiliated Hospital of Anhui Medical University dataset. High expression of LINC00183 was correlated with poorer overall survival and progression-free survival of T-LBL patients compared to those with low expression of LINC00183. Furthermore, miR-371b-5p was negatively regulated by LINC00183. In vivo and in vitro assays showed that LINC00183-mediated T-LBL chemoresistance depended on miR-371b-5p expression. The direct binding of miR-371b-5p to Smad2 and LEF1 was verified by luciferase assays. It was shown that TCF4/LEF1 could bind to the LINC00183 promoter site and increase its transcript level. Downregulation of miR-371b-5p led to increased expression of Smad2/LEF1, and in turn increased LINC00183 expression. Additionally, phospho-Smad2 promotes nuclear translocation of β-catenin, LINC00183 downregulation decreased chemoresistance induced by β-catenin and TGF-β1 in T-LBL cells. We unraveled a β-catenin-LINC00183-miR-371b-5p-Smad2/LEF1 feedback loop that promotes T-LBL progression and chemoresistance, indicating that LINC00183 may serve as a potential therapeutic target in T-LBLs. The online version contains supplementary material available at 10.1186/s13046-023-02670-9.
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DOI：
10.1038/nrc.2017.99
发表时间：
2018-01
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Anastasiadou E;Jacob LS;Slack FJ
通讯作者：
Slack FJ
长链非编码 RNA 在癌症中的作用、功能和机制。
DOI：
10.1016/j.gpb.2015.09.006
发表时间：
2016-02
期刊：
Genomics, proteomics & bioinformatics
影响因子：
--
作者：
Fang Y;Fullwood MJ
通讯作者：
Fullwood MJ
影响因子：
4.8
作者：
DiRenzo DM;Chaudhary MA;Shi X;Franco SR;Zent J;Wang K;Guo LW;Kent KC
通讯作者：
Kent KC
影响因子：
16.2
作者：
Tian, Xiao-Peng;Cai, Jun;Cai, Qing-Qing
通讯作者：
Cai, Qing-Qing
用于预测成人 T 细胞淋巴母细胞淋巴瘤复发的 CpG 甲基化分类器
影响因子：
11.5
作者：
Tian, Xiao-Peng;Su, Ning;Cai, Qing-Qing
通讯作者：
Cai, Qing-Qing