当前位置: X-MOL 学术Theranostics › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers.
Theranostics ( IF 12.4 ) Pub Date : 2020-8-21 , DOI: 10.7150/thno.40944
Lei Wang 1, 2, 3 , Guan-Tian Lang 1, 2, 3 , Meng-Zhu Xue 4 , Liu Yang 1, 2, 3 , Li Chen 1, 2, 3 , Ling Yao 1, 2, 3 , Xiao-Guang Li 1, 2, 3 , Peng Wang 5, 6 , Xin Hu 1, 2, 3 , Zhi-Ming Shao 1, 2, 3, 7
Affiliation  

Background: Triple-negative breast cancer (TNBC) is an aggressive malignancy with high heterogeneity. However, the alternative polyadenylation (APA) profiles of TNBC remain unknown. Here, we aimed to define the characteristics of the APA events at post-transcription level among TNBCs./nMethods: Using transcriptome microarray data, we analyzed APA profiles of 165 TNBC samples and 33 paired normal tissues. A pooled short hairpin RNA screen targeting 23 core cleavage and polyadenylation (C/P) genes was used to identify key C/P factors./nResults: We established an unconventional APA subtyping system composed of four stable subtypes: 1) luminal androgen receptor (LAR), 2) mesenchymal-like immune-activated (MLIA), 3) basal-like (BL), 4) suppressed (S) subtypes. Patients in the S subtype had the worst disease-free survival comparing to other patients (log-rank p = 0.021). Enriched clinically actionable pathways and putative therapeutic APA events were analyzed among each APA subtype. Furthermore, CPSF1 and PABPN1 were identified as the master C/P factors in regulating APA events and TNBC proliferation. The depletion of CPSF1 or PABPN1 weakened cell proliferation, enhanced apoptosis, resulted in cell cycle redistribution and a reversion of APA events of genes associated with tumorigenesis, proliferation, metastasis and chemosensitivity in breast cancer./nConclusions: Our findings advance the understanding of tumor heterogeneity regulation in APA and yield new insights into therapeutic target identification in TNBC.

中文翻译:

剖析三阴性乳腺癌中备选聚腺苷酸谱的异质性。

背景:三阴性乳腺癌(TNBC)是具有高度异质性的侵袭性恶性肿瘤。但是,TNBC的替代聚腺苷酸化(APA)资料仍然未知。在这里,我们旨在定义TNBC之间转录后水平的APA事件的特征。/n方法:使用转录组微阵列数据,我们分析了165个TNBC样品和33个配对的正常组织的APA谱。针对23个核心切割和聚腺苷酸化(C / P)基因的汇集的短发夹RNA筛选用于鉴定关键C / P因子我们建立了由四个稳定亚型组成的非常规APA亚型系统:1)腔雄激素受体(LAR),2)间充质样免疫激活(MLIA),3)基底样(BL),4)抑制型(S) 。与其他患者相比,S亚型患者的无病生存期最差(对数秩p = 0.021)。在每个APA亚型中分析了丰富的临床可行途径和假定的治疗性APA事件。此外,CPSF1和PABPN1被确定为调节APA事件和TNBC增殖的主要C / P因子。CPSF1或PABPN1的耗竭减弱了细胞的增殖,增强了细胞凋亡,导致了细胞周期的重新分布以及与乳腺癌的肿瘤发生,增殖,转移和化学敏感性相关的基因的APA事件的逆转。结论:我们的发现促进了对APA中肿瘤异质性调控的理解,并为TNBC中的治疗靶标鉴定提供了新的见解。
更新日期:2020-08-27
down
wechat
bug