内皮素受体 B 在肝细胞癌中的临床意义及其潜在的分子机制。
The clinical significance of endothelin receptor type B in hepatocellular carcinoma and its potential molecular mechanism.
机构信息
Department of Pathology, First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region 530021, PR China.
Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region 530021, PR China.
出版信息
Exp Mol Pathol. 2019 Apr;107:141-157. doi: 10.1016/j.yexmp.2019.02.002. Epub 2019 Feb 12.
OBJECTIVE
To explore the clinical significance and potential molecular mechanism of endothelin receptor type B (EDNRB) in hepatocellular carcinoma (HCC).
METHODS
Immunohistochemistry was used to detect EDNRB protein expression level in 67 HCC paraffin embedded tissues and adjacent tissues. Correlations between EDNRB expression level and clinicopathologic parameters were analyzed in our study. The expression level and clinical significance of EDNRB in HCC were also evaluated from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The cBioPortal for Cancer Genomics was employed to analyze the EDNRB related genes, and Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network were conducted for those EDNRB related genes.
RESULTS
Lower expression level of EDNRB in HCC was verified by immunohistochemistry than adjacent tissues (P < 0.0001). The expression level of EDNRB in HCC tissues was lower than normal control liver tissues based on TCGA and GEO data (standard mean difference [SMD] = -1.48, 95% [confidence interval] CI: -1.63-(-1.33), P = 0.116, I = 32.4%). Kaplan-Meier analysis showed that HCC patients with lower EDNRB expression were more prone to poor prognosis (P = .0041). The top terms of GO annotation in biological process, cellular component and molecular function were vasculature development, actin filament and transmembrane receptor protein kinase activity, respectively. The KEGG pathway enrichment analysis confirmed that EDNRB related genes mainly participated in Vascular smooth muscle contraction, cGMP-PKG signaling pathway and Focal adhesion pathways. The result of PPI network construction showed that KDR, VEGFC, FLT1, CDH5 and ADCY4 were possible to become the core genes of EDNRB related genes, which need further experiments to confirm.
CONCLUSION
Our study provides novel findings and insights on the molecular pathogenesis of HCC from EDNRB view.
目的
探讨内皮素受体 B（EDNRB）在肝细胞癌（HCC）中的临床意义和潜在分子机制。
方法
采用免疫组织化学方法检测 67 例 HCC 石蜡包埋组织及其相邻组织中 EDNRB 蛋白的表达水平。分析 EDNRB 表达水平与临床病理参数的相关性。本研究还从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）评估 EDNRB 在 HCC 中的表达水平和临床意义。利用 cBioPortal for Cancer Genomics 分析 EDNRB 相关基因，并对这些 EDNRB 相关基因进行基因本体（GO）注释、京都基因与基因组百科全书（KEGG）通路富集分析和蛋白质-蛋白质相互作用（PPI）网络分析。
结果
免疫组织化学结果显示 HCC 中 EDNRB 的表达水平低于相邻组织（P<0.0001）。基于 TCGA 和 GEO 数据，HCC 组织中 EDNRB 的表达水平低于正常对照肝组织（标准均数差 [SMD]=-1.48，95%置信区间 [CI]：-1.63-(-1.33)，P=0.116，I=32.4%）。Kaplan-Meier 分析表明，EDNRB 低表达的 HCC 患者预后较差（P=0.0041）。GO 注释在生物学过程、细胞成分和分子功能中的主要术语分别为血管发育、肌动蛋白丝和跨膜受体蛋白激酶活性。KEGG 通路富集分析证实，EDNRB 相关基因主要参与血管平滑肌收缩、cGMP-PKG 信号通路和黏附斑通路。PPI 网络构建结果表明，KDR、VEGFC、FLT1、CDH5 和 ADCY4 可能成为 EDNRB 相关基因的核心基因，尚需进一步实验验证。
结论
本研究从 EDNRB 角度为 HCC 的分子发病机制提供了新的发现和见解。
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