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首页> 外文期刊>EBioMedicine >Aspirin targets P4HA2 through inhibiting NF-κB and LMCD1-AS1/let-7g to inhibit tumour growth and collagen deposition in hepatocellular carcinoma
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Aspirin targets P4HA2 through inhibiting NF-κB and LMCD1-AS1/let-7g to inhibit tumour growth and collagen deposition in hepatocellular carcinoma

机译：阿司匹林通过抑制NF-κB和LMCD1-AS1 / let-7g靶向P4HA2，从而抑制肝细胞癌的肿瘤生长和胶原沉积

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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-κB/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-κB 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. Funds 973 Program, National Natural Scientific Foundation of China, Fundamental Research Funds for the Central Universities, Project of Prevention and Control of Key Chronic Non-Infectious Diseases.
机译：背景技术细胞外基质（ECM）的异常构建与癌变和实体瘤尤其是肝细胞癌（HCC）的发展密切相关。作为ECM的主要成分，胶原蛋白在癌变过程中起着举足轻重的作用。 P4HA2是胶原蛋白形成过程中必不可少的酶，已成为HCC治疗中的重要靶标。在这里，我们试图破译经典的消炎药阿司匹林（ASA）是否可以通过靶向P4HA2来改善HCC的预后。方法采用蛋白质印迹法，qRT-PCR法，免疫荧光染色法，荧光素酶报告基因法和ChIP法检测阿司匹林调节P4HA2表达的分子机制。使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化分析，通过靶向NF-κB/ P4HA2轴和LMCD1-AS1 / let-7g / P4HA2轴，评估阿司匹林的抗纤维化作用。体内。 TCGA数据库用于评估P4HA2，let-7g，LMCD1-AS1与HCC患者总生存率之间的相关性。在异种移植小鼠中，阿司匹林能够靶向P4HA2以减少胶原蛋白沉积，从而抑制肝肿瘤的生长。 TCGA数据库分析显示，HCC患者中较高的P4HA2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的联系。从机制上讲，NF-κB可以与P4HA2的启动子结合以激活其转录。此外，lncRNA LMCD1-AS1充当let-7g的分子海绵，以转录后诱导let-7g的靶基因即P4HA2。解释我们的发现揭示了阿司匹林通过破坏异常胶原沉积而在抑制HCC中的新作用和调节机制。国家自然科学基金面上项目“ 973计划”，中央大学基础研究基金，“慢性非传染病重点防治项目”。

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