Wen Quan, Wang Dong, Yang Yao, Chen Xianhua, Pan Xiaodong, Han Qi, Deng Youcai, Li Xiaohui, Chen Xianhua, Yan Jun, Zhou Jihong
Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
State Key Laboratory of Trauma, Burns and Combined Injury, Institute for Traffic Medicine, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
J Tradit Chin Med. 2017 Aug;37(4):510-521.
To profile the liver cancer specific long noncoding RNAs (lncRNAs) and competing endogenous RNA (ceRNA) networks of Hepatitis B virus (HBV)-associated hepatocarcinogensis (HCG) and to examine the effect of compound K on the expression of identified ceRNA networks.
Based on lncRNA and messenger RNA (mRNA) microarray data of HBV-associated liver cancer, the current study profiles the cancer specific lncRNAs and ceRNA networks of HBV-associated HCG through comprehensive application of RegRNA 2, miRTarBase and Pearson correlation coefficient analysis. Compound K-treated liver cancer cells were harvested for analysis of transcriptional levels of both enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH)-AS1 and ENTPD5.
The results revealed that 11 Encyclopedia of DNA Elements annotated lncRNAs were differentially expressed in the process of HBV-associated HCG. Among these lncRNAs, 95 potential ceRNA networks with highly positively correlated expression profiles between the interacting lncRNAs and mRNAs (Pearson correlation coefficient > 0.7) were constructed. Of note, two HBV-associated ceRNA networks, EHHADH-AS1-hsa-miR-4459-ectonucleoside triphosphate diphosphohydrolase 5 and LINC01018-hsa-miRNA-574-5p-glucose-6-phosphatase catalytic subunit, with Pearson correlation coefficient > 0.9, may play a critical role in hepatocellular carcinoma development, which was supported by experimental evidence. Interestingly, compound K, an intestinal bacterial metabolite of ginseng protopanaxadiol saponin, which has been proven to promote apoptosis of human hepatocellular carcinoma cells, was found to impede the down-regulation of EHHADH-AS1 in several liver cancer cell lines including HepG3B, Huh-7 and plc/prf/5 cells.
Comprehensive application of co-expression network analysis and prediction of RNA interaction may be a feasible strategy to unravel the potential ceRNA networks involved in the process of human diseases.
剖析乙型肝炎病毒（HBV）相关肝癌发生（HCG）过程中肝癌特异性长链非编码RNA（lncRNA）和竞争性内源RNA（ceRNA）网络，并检测化合物K对所鉴定ceRNA网络表达的影响。
基于HBV相关肝癌的lncRNA和信使核糖核酸（mRNA）微阵列数据，本研究通过综合应用RegRNA 2、miRTarBase和Pearson相关系数分析，剖析HBV相关HCG的癌症特异性lncRNA和ceRNA网络。收集经化合物K处理的肝癌细胞，用于分析烯酰辅酶A水合酶和3-羟酰基辅酶A脱氢酶（EHHADH）-AS1及ENTPD5的转录水平。
结果显示，11个DNA元件百科全书注释的lncRNA在HBV相关HCG过程中差异表达。在这些lncRNA中，构建了95个潜在的ceRNA网络，其相互作用的lncRNA与mRNA之间具有高度正相关的表达谱（Pearson相关系数>0.7）。值得注意的是，两个HBV相关的ceRNA网络，即EHHADH-AS1-hsa-miR-4459-外核苷三磷酸二磷酸水解酶5和LINC01018-hsa-miRNA-574-5p-葡萄糖-6-磷酸酶催化亚基，Pearson相关系数>0.9，可能在肝细胞癌发生发展中起关键作用，实验证据支持了这一点。有趣的是，化合物K是人参原人参二醇皂苷的肠道细菌代谢产物，已被证明可促进人肝癌细胞凋亡，发现在包括HepG3B、Huh-7和plc/prf/5细胞在内的几种肝癌细胞系中，它可阻止EHHADH-AS1的下调。
共表达网络分析和RNA相互作用预测的综合应用可能是揭示人类疾病过程中潜在ceRNA网络的可行策略。
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