在全世界，肝細胞癌是常見並且致命的惡性腫瘤。在過去，大多數的肝細胞癌患者都是由病毒感染演變，像是B型肝炎跟C型肝炎。然而近期的抗病毒療法有效的降低B型肝炎跟C型肝炎的患者數目，並且肝細胞癌中由病毒感染發展的患病率明顯地下降。有趣的是因為其他肝臟疾病發展成肝細胞癌的患病相關性也增加，所以在全世界肝癌的總患病率仍然維持在一個穩定的水平。因此，在肝細胞癌的研究中，探討正常的肝臟細胞演變到肝癌經由其他肝臟疾病的肝癌化過程是當務之急。
基於我們提出的系統生物方法，我們建立各個肝臟疾病的全基因組的基因和表觀遺傳網路 (GEN) 並且進一步的從不同肝臟狀況的GENs中萃取出各自的核心基因和表觀遺傳網路。此外，藉由比較正常肝臟細胞以及肝臟疾病的核心基因和表觀遺傳網路，我們能進一步選出特異核心網路的標誌物去研究正常肝臟細胞到肝細胞癌的演變機制。藉由更深入的探討特異核心網路，我們能得到正常的肝臟細胞演變到肝細胞癌經由其他肝臟疾病癌化過程的分子機制觀點。所以，我們識別出正常肝臟細胞到肝細胞癌經由非酒精性脂肪肝疾病(NAFLD)&非酒精性脂肪肝炎(NASH)的肝癌化過程主要可以被Wnt信號通路和MAPK信號通路通過HIST2H2BE、HSPB1、RPL30和ALDOB的DNA甲基化以及miR-21和miR-122的調控所誘導，這些可以做為肝癌化過程中的潛在複合藥物標靶。並且我們還識別出正常肝臟細胞到肝細胞癌經由原發性膽汁性肝硬化(PBC)&原發性硬化性膽管炎(PSC)的肝癌化過程主要可以被Wnt信號通路和MAPK信號通路通過RPL23A、HIST2H2BE、TIMP1、IGF2、RPL30和ALDOB的DNA甲基化以及miR-29a、miR-21和miR-122的調控所誘導，這些可以做為肝癌化過程中的潛在複合藥物標靶。最後，一個包含lactacystin、OGX-427、DIHYDROXYACETONE PHOSPHATE、curcumin 和quercetin的複合分子藥物被用來抑制NAFLD&NASH這類型肝臟疾病的肝癌化過程通過標靶上述的複合藥物標靶。另一個包含lactacystin、L-(-)-3-Phenyllactic acid、DIHYDROXYACETONE PHOSPHATE、batimastat、mannose 6-phosphate、curcumin 、quercetin和ellagic acid的複合分子藥物被用來抑制PBC&PSC這類型肝臟疾病的肝癌化過程通過標靶上述的複合藥物標靶。

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

致謝 i
摘要 ii
Abstract iv
Contents vi
List of Figures vii
List of Tables viii
List of Supplemental materials viii
Introduction 1
Materials and Methods 7
2.1 Overview of the construction for genome-wide GENs, core GENs and specific core networks of genesis and hepatocarcinogenesis of HCC 7
2.2 Big data mining and preprocessing of both expression data and methylation data for liver diseases and HCC 8
2.3 Constructing genome-wide candidate genetic-and-epigenetic network 10
2.4 Constructing protein-protein interaction network (PPIN) and gene regulatory network (GRN) by system modeling method via microarray data and NGS data 10
2.5 Parameter estimation of candidate PPIN and GRN by the constrained least square estimation method and system order detection scheme 13
2.6 Determining significant GEN structures (core GENs) of the different liver diseases via Principal network projection (PNP) 18
2.7 Drug mining and design for NAFLD&NASH-developed HCC and PBC&PSC-developed HCC through the investigations of key network biomarkers of progression mechanisms in Figure 9 20
Results 22
3.1 Analysis of specific core networks to investigate underlying cellular mechanisms for genesis and hepatocarcinogenesis in the upper progression path of Figure 1 24
3.2 Analysis of specific core networks to investigate underlying cellular mechanisms for genesis and hepatocarcinogenesis in the lower progression path of Figure 1 27
3.3 The progression molecular mechanism based on specific core networks in the upper progression path and the lower progression path of Figure 1 31
Discussion 35
4.1 Dysregulations of DNA methylation and miRNA regulation contribute to genesis and hepatocarcinogenesis from normal liver cell to HCC through NAFLD&NASH or PBC&PSC 36
4.1.1 Dysregulations of DNA methylation and miR-21 contribute to genesis and hepatocarcinogenesis from the upper progression path to HCC in Figure 1 36
4.1.2 Dysregulations of DNA methylation, miR-21, miR-122 and miR-29a, contribute to genesis and hepatocarcinogenesis from the lower progression path to HCC in Figure 1 38
4.1.3 Dysregulation of miR-21, miR-122 and miR-29a contribute to human HCC tumor progression 39
4.2 Multiple molecules drug design for NAFLD&NASH-developed HCC and PBC&PSC-developed HCC by integrating the detailed investigations of progression mechanisms and drug databases 41
Conclusion 43

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