Systems Biology Approach To Investigate The Molecular Mechanisms Of HCC And Therapeutic Effect Of Hugan Tablet Formula

Hepatocellular Carcinoma(HCC) is one of the most common malignancies in the clinic, which mainly resulted from various risk factors including HBV, HCV, cirrhosis, environment pollution, various stimulation and so on. Indeed, about 80% cases of liver cancer arise along with cirrhotic livers and about one-third of all liver cancers occurring in the world are attributed to HCV. Therefore, hepatocellular damage progressing from chronic hepatitis to cirrhosis to HCC was developed, especially when the HCC is induced by HCV, which is more complicated. Although many investigations showed the close relationship among HCV, cirrhosis and HCC, the mechanism was still unclear. There are great challenges in the diagnosis and therapy of HCC.In this research, we attempted to explore the mechanism of cirrhosis induced HCC by analyzing the data of gene microarray, mi RNA microarray and DNA methylation microarray. 120 differential expression genes, 32 differential expression miRNAs and 34 genes whose methylation level changed were screened. Meanwhile, the differential co-expression genes were identified by calculating the correlation coefficient between genes associated with hepatitis C cirrhosis and HCC respectively. In order to further understand the interactions of those HCC related genes, the PPI mapping was used to expand the potential disease-related genes. Then, a integrated transcription network was developed, consisting of all those possible related genes, differential expression mi RNAs and transcription factors. After a topology analysis to the network, 130 hub nodes were obtained, including 8 miRNAs, 63 differential co-expression genes, 6 methylation level changed genes, 8 transcription factors and 46 PPI mapping genes, which were considered to play important roles in investigate the mechanism from cirrhosis to HCC. Finally, GO functional enrichment and pathway enrichment were performed to these 130 hub nodes and the results indicated that the function of these nodes mainly were invovled with regulation of macromolecule metabolic process, biosynthetic process, protein kinase cascade, regulation of cell death etc. and the process of cirrhosis to HCC mainly were related to pathways in cancer, neurotrophin signaling pathway, T cell receptor signaling pathway, MAPK signaling pathway, cell cycle, Toll-like receptor signaling pathway etc.Hu Gan tablet is one of formulas in Chinese Pharmacopoeia(2015), which have great threapy effects on the liver diseases. This formula is composed of 6 Chines herbs: radix bupleuri(Chaihu), capillary Artemisia(Yinchen), radix isatidis(Banlangen), Schisandra chinensis(Wuweizi),Porcine Bile Extract(Zhudanfen) and Phaseolus radiates(Lvdou). The methods of TCM systems pharmacology were performed to illustrate the potential treatment mechanisms of this formula: ADME screening of the active components, target prediction by using machine learning methods, network construction and analysis. The compound-target network suggested single compound connected with multi-targets and single target also connected with multi-compounds to treat the diseases effectively, which is consistent with the western medcine. Moreover, we conducted PPI mapping to the potential targets and attempted to analyse their functions by GO functional enrichment and Pathway enrichment, in which many tumor-related genes and pathways were found.Consequently, we compared the two networks to further understand the mechanisms of cirrhosis to HCC. Interestingly, the two networks have similar characteristics: of the 101 shared nodes, 16 hub nodes such as EGFR, GRB2, PIK3R1, TRAF2 and so on were involved with cancer; In the GO functional enrichment analysis, there are over 111 GO terms(90 Biological Process, 11 Molecular Function, 10 Cellular Component); In the pathway enrichment analysis, 11 shared pathways were related with cancer significantly. This similarity further proved the therapy effects on liver diseases of Hu Gan Tablet.In summary, from a systems level, the interaction among the genes, transcription factor, miRNA and methylation related to cirrhosis-HCC process was analyzed in this work, and meanwhile we investigated the mechanisms how HuGan tablet therapies cirrhosis to delay the occurrence of HCC through its characteristics of muti-components and muti-targets.