Aspirin targets P4HA2 through inhibiting NF-κB and LMCD1-AS1/let-7g to inhibit tumour growth and collagen deposition in hepatocellular carcinoma
Aspirin targets P4HA2 through inhibiting NF-κB and LMCD1-AS1/let-7g to inhibit tumour growth and collagen deposition in hepatocellular carcinoma
复制标题
阿司匹林通过抑制NF-κB和LMCD1-AS1/let-7g靶向P4HA2抑制肝细胞癌肿瘤生长和胶原沉积
DOI：
10.1016/j.ebiom.2019.06.048
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发表时间：
2019-07-01
期刊：
影响因子：
11.1
通讯作者：
Ye, Lihong
中科院分区：
文献类型：
--
作者：
Wang, Tianjiao;Fu, Xueli;Ye, Lihong
背景资料：细胞外基质（ECM）的异常构建与实体瘤，特别是肝细胞癌（HCC）的发生和发展密切相关。胶原作为ECM的主要成分，在肿瘤发生中起着关键作用。P4 HA 2是胶原形成过程中的关键酶，成为肝癌治疗的重要靶点。本研究旨在探讨经典抗炎药阿司匹林（阿萨）是否能通过靶向P4 HA 2改善肝癌患者的预后。方法：采用Western blotting、qRT-PCR、免疫荧光染色、荧光素酶报告基因检测和ChIP等方法，研究阿司匹林调控P4 HA 2表达的分子机制。采用小鼠异种移植模型、细胞活力测定、集落形成测定和免疫组织化学分析来评价阿司匹林通过靶向NF-κ B/P4 HA 2轴和LMCD 1-AS 1/let-7 g/P4 HA 2轴在体外和体内的抗纤维化作用。TCGA数据库被用来评估之间的相关性P4 HA 2，let-7 g，LMCD 1-AS 1和HCC patients.Findings的总生存率：在异种移植小鼠，阿司匹林能够靶向P4 HA 2，以减少胶原沉积，从而抑制肝脏肿瘤的生长。TCGA数据库分析显示，肝癌患者中较高的P4 HA 2浓度与较短的总生存期或较高的癌症分期和病理分级之间存在密切关系。从机制上讲，NF-κ B可以与P4 HA 2的启动子结合以激活其转录。此外，lncRNA LMCD 1-AS 1还作为let-7 g的分子海绵，在转录后诱导let-7 g的靶基因P4 HA 2表达。(C)2019作者由爱思唯尔公司出版
Background: Abnormal construction of the extracellular matrix (ECM) is intimately linked with carcinogenesis and the development of solid tumours, especially hepatocellular carcinoma (HCC). As the major component of the ECM, collagen plays a pivotal role in carcinogenesis. P4HA2, the essential enzyme during collagen formation, becomes an important target in HCC treatment. Here, we tried to decipher whether aspirin (ASA), a classic anti-inflammatory drug, could improve the prognosis of HCC through targeting P4HA2.Methods: Western blotting, qRT-PCR assay, immunofluorescence staining, luciferase reporter gene assay, and ChIP assay were applied to demonstrate the molecular mechanism of the regulation of P4HA2 expression by aspirin. A mouse xenograft model, cell viability assay, colony formation assay, and immunohistochemistry analysis were used to evaluate the anti-fibrosis effect of aspirin through targeting the NF-kappa B/P4HA2 axis and LMCD1-AS1/let-7g/P4HA2 axis in vitro and in vivo. The TCGA database was used to evaluate the correlation among P4HA2, let-7g, LMCD1-AS1 and overall survival of HCC patients.Findings: In xenograft mice, aspirin was capable of targeting P4HA2 to decrease collagen deposition, resulting in the inhibition of liver tumour growth. TCGA database analysis revealed the close association between a higher P4HA2 concentration in HCC patients and shorter overall survival or a higher cancer stage and the pathological grade. Mechanistically, NF-kappa B can bind to the promoter of P4HA2 to activate its transcription. Moreover, lncRNA LMCD1-AS1 functions as a molecular sponge of let-7g to post-transcriptionally induce the target gene of let-7g, namely, P4HA2.Interpretation: Our findings disclose the novel role and regulatory mechanism of aspirin in the suppression of HCC by disrupting abnormal collagen deposition. (C) 2019 The Authors. Published by Elsevier B.V.