Abstract
Hepatocellular carcinoma (HCC) is common and deadly malignancy worldwide. In the past, most HCC patients were developed by viral infection such as hepatitis B virus (HBV) or hepatitis C virus (HCV). However, antiviral therapy has much influenced on the reduction of patients with HBV and HCV recently, and the prevalence of viral infection development of HCC is obviously decreased. Intriguingly, the total prevalence of HCC is still maintained in a stable level worldwide due to other liver diseases being developed to HCC to increase prevalence correspondingly. Hence, investigating hepatocarcinogenesis from normal liver cell to liver cancer through other liver diseases is a priority in HCC research. Based on the proposed systems biology approach, we constructed genome-wide genetic-and-epigenetic networks (GENs) and further extracted core genetic-and-epigenetic networks from their GENs at different liver conditions. Moreover, we further selected specific core network markers by comparing core genetic-and-epigenetic networks of normal liver cell and liver diseases to investigate progression mechanisms from normal liver cells to HCC. By further investigating specific core networks, we could get insight into the molecular mechanisms of hepatocarcinogenesis from normal liver cell to HCC through different liver diseases. Furthermore, we identified that the hepatocarcinogenesis from normal liver cell to HCC through nonalcoholic fatty liver disease (NAFLD)& nonalcoholic steatohepatitis (NASH) can be induced mainly by WNT signaling pathway and MAPK signaling pathway through DNA methylation of HIST2H2BE, HSPB1, RPL30 and ALDOB, and the regulations of miR-21 and miR-122, to be potential multiple drug targets of the hepatocarcinogenesis. And we also identified that the hepatocarcinogenesis from normal liver cell to HCC through primary biliary cirrhosis (PBC)& primary sclerosing cholangitis (PSC) can be induced mainly by WNT signaling pathway and MAPK signaling pathway through DNA methylation of RPL23A, HIST2H2BE, TIMP1, IGF2, RPL30 and ALDOB, and the regulations of miR-29a, miR-21 and miR-122, to be potential multiple drug targets too. Finally, a multiple molecules drug comprising lactacystin, OGX-427, DIHYDROXYACETONE PHOSPHATE, curcumin and quercetin was proposed to target the above multiple drug targets for inhibiting the hepatocarcinogenesis through NAFLD&NASH liver diseases. Another multiple molecules drug comprising lactacystin, L-(-)-3-Phenyllactic acid, DIHYDROXYACETONE PHOSPHATE, batimastat, mannose 6-phosphate, curcumin, quercetin and ellagic acid was also proposed to target the above multiple drug targets for inhibiting the hepatocarcinogenesis through PBC&PSC liver diseases. Keywords: HCC、liver diseases、 miRNA、DNA methylation、big database mining、genetic and epigenetic network (GEN)、genesis、hepatocarcinogenesis、molecular mechanism、multiple drug targets、multiple molecules drug