Competing endogenous RNA screening based on long noncoding RNA-messenger RNA co-expression profile in Hepatitis B virus-associated hepatocarcinogenesis

OBJECTIVE： To profile the liver cancer specific long noncoding RNAs（lnc RNAs） and competing endogenous RNA（ce RNA） networks of Hepatitis B virus（HBV）-associated hepatocarcinogensis（HCG） and to examine the effect of compound K on the expression of identified ce RNA networks.METHODS： Based on lnc RNA and messenger RNA（m RNA） microarray data of HBV-associated liver cancer, the current study profiles the cancer specific lnc RNAs and ce RNA networks of HBV-associated HCG through comprehensive application of Reg RNA 2, mi RTar Base and Pearson correlation coefficient analysis. Compound K-treated liver cancer cells were harvested for analysis of transcriptional levels of both enoyl-Co A hydratase and 3-hydroxyacyl Co A dehydrogenase（EHHADH）-AS1 and ENTPD5.RESULTS： The results revealed that 11 Encyclopedia of DNA Elements annotated lnc RNAs were differentially expressed in the process of HBV-associated HCG. Among these lnc RNAs, 95 potential ce RNA networks with highly positively correlated expression profiles between the interacting lnc RNAs and m RNAs（Pearson correlation coefficient ≥ 0.7） were constructed. Of note, two HBV-associated ce RNA networks, EHHADH-AS1-hsa-mi R-4459-ectonucleoside triphosphate diphosphohydrolase 5 and LINC01018-hsa-mi RNA-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 Hep G3 B, Huh-7 and plc/prf/5 cells.CONCLUSION： Comprehensive application of co-expression network analysis and prediction of RNA interaction may be a feasible strategy to unravel the potential ce RNA networks involved in the process of human diseases.