Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 2018, 8635329
eCollection

Investigating Pathogenic and Hepatocarcinogenic Mechanisms From Normal Liver to HCC by Constructing Genetic and Epigenetic Networks via Big Genetic and Epigenetic Data Mining and Genome-Wide NGS Data Identification

Affiliations

Investigating Pathogenic and Hepatocarcinogenic Mechanisms From Normal Liver to HCC by Constructing Genetic and Epigenetic Networks via Big Genetic and Epigenetic Data Mining and Genome-Wide NGS Data Identification

Cheng-Wei Li et al. Dis Markers.

Abstract

The prevalence of hepatocellular carcinoma (HCC) is still high worldwide because liver diseases could develop into HCC. Recent reports indicate nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NAFLD&NASH) and primary biliary cirrhosis and primary sclerosing cholangitis (PBC&PSC) are significant of HCC. Therefore, understanding the cellular mechanisms of the pathogenesis and hepatocarcinogenesis from normal liver cells to HCC through NAFLD&NASH or PBC&PSC is a priority to prevent the progression of liver damage and reduce the risk of further complications. By the genetic and epigenetic data mining and the system identification through next-generation sequencing data and its corresponding DNA methylation profiles of liver cells in normal, NAFLD&NASH, PBC&PSC, and HCC patients, we identified the genome-wide real genetic and epigenetic networks (GENs) of normal, NAFLD&NASH, PBC&PSC, and HCC patients. In order to get valuable insight into these identified genome-wide GENs, we then applied a principal network projection method to extract the corresponding core GENs for normal liver cells, NAFLD&NASH, PBC&PSC, and HCC. By comparing the signal transduction pathways involved in the identified core GENs, we found that the hepatocarcinogenesis through NAFLD&NASH was induced through DNA methylation of HIST2H2BE, HSPB1, RPL30, and ALDOB and the regulation of miR-21 and miR-122, and the hepatocarcinogenesis through PBC&PSC was induced through DNA methylation of RPL23A, HIST2H2BE, TIMP1, IGF2, RPL30, and ALDOB and the regulation of miR-29a, miR-21, and miR-122. The genetic and epigenetic changes in the pathogenesis and hepatocarcinogenesis potentially serve as potential diagnostic biomarkers and/or therapeutic targets.

Figures

Figure 1
Figure 1
(a) Progression path in pathogenesis and hepatocarcinogenesis. (b) Flowchart for identifying core GENs and pathways.
Figure 2
Figure 2
Signaling pathways for investigating cellular mechanisms of progression for pathogenesis from NAFLD&NASH to HCC. The blue dash-dotted lines and the yellow dotted lines represent the specific edges of the real GENs, including PPINs and GRNs, in NAFLD&NASH and HCC, respectively; the green solid lines denote the common edges between NAFLD&NASH and HCC; the red and black symbols indicate specific core members of the real GENs in NAFLD&NASH and HCC, respectively; and the green symbols are the common core members between NAFLD&NASH and HCC. In this figure, these core members are padded to complete the relevant signaling pathways for the convenience of analysis. The cytosolic proteins involved in the MAPK and the WNT pathways were highlighted by light-gray and light-blue bands, respectively. Dysfunctions of both metabolism and apoptosis via DNA hypermethylation and dysregulation of miR-21 contribute to tumorigenesis from NAFLD&NASH to HCC. Dysregulation of miR-21 and miR-122 contributes to tumor invasion and metastasis in HCC.
Figure 3
Figure 3
Signaling pathways for investigating cellular mechanisms of progression for pathogenesis from normal to PBC&PSC. The orange dotted lines and the blue dash-dotted lines represent the specific edges of the real GENs, including PPINs and GRNs, in normal and PBC&PSC, respectively; the green solid lines denote the common edges between normal and PBC&PSC; the blue and black symbols indicate specific core members of the real GENs in normal and PBC&PSC, respectively; and the green symbols are the common core members between normal and PBC&PSC. In this figure, these core members are padded to complete the relevant signaling pathways for the convenience of analysis. The cytosolic proteins involved in the MAPK and the WNT pathways were highlighted by light-green and light-blue bands, respectively. Defect of autoimmune response via DNA hypomethylation contributes to the dysfunction of DNA repair and gives rise to PBC&PSC. Dysregulation of miR-21 and miR-122 contributes to the dysfunction of apoptosis and autoimmune in PBC&PSC, respectively.
Figure 4
Figure 4
Signaling pathways for investigating cellular mechanisms of progression for pathogenesis from PBC&PSC to HCC. The blue dash-dotted lines and the yellow dotted lines represent the specific edges of the real GENs, including PPINs and GRNs, in PBC&PSC and HCC, respectively; the green solid lines denote the common edges between PBC&PSC and HCC; the red and black symbols indicate specific core members of the real GENs in PBC&PSC and HCC, respectively; and the green symbols are the common core members between PBC&PSC and HCC. In this figure, these core members are padded to complete the relevant signaling pathways for the convenience of analysis. The cytosolic proteins involved in the MAPK and the WNT pathways were highlighted by light-green and light-blue bands, respectively. Dysfunction of metabolism process, apoptosis, and autoimmune via DNA hypermethylation, and dysregulations of miR-21, miR-122, and miR-29a contribute to tumorigenesis from PBC&PSC to HCC. Dysregulation of miR-21, miR-122, and miR-29a contributes to tumor invasion and metastasis in HCC.
Figure 5
Figure 5
Signaling pathways for investigating cellular mechanisms of progression for pathogenesis from normal to NAFLD&NASH. The orange dotted lines and the blue dash-dotted lines represent the specific edges of the real GENs, including PPINs and GRNs, in normal and NAFLD&NASH, respectively; the green solid lines denote the common edges between normal and NAFLD&NASH; the blue and black symbols indicate specific core members of the real GENs in normal and NAFLD&NASH, respectively; and the green symbols are the common core members between normal and NAFLD&NASH. In this figure, these core members are padded to complete the relevant signaling pathways for the convenience of analysis. The cytosolic proteins involved in the MAPK and the WNT pathways were highlighted by light-gray and light-blue bands, respectively. Dysfunction of DNA repair via DNA hypermethylation and hepatic triglyceride excessive accumulation results in the pathogenesis of NAFLD&NASH. Dysregulation of miR-21 contributes to the dysfunction of apoptosis in NAFLD&NASH.
Figure 6
Figure 6
Progression mechanisms for the pathogenesis of NAFLD&NASH and the hepatocarcinogenesis through NAFLD&NASH. The blue, red, green, and yellow lines represent the interactions (or regulations) in NAFLD&NASH pathogenesis, NAFLD&NASH hepatocarcinogenesis, the hepatocarcinogenesis of normal liver through NAFLD&NASH, and the aggressive tumor progression, respectively, based on Figures 5 and 2. The epigenetic modification of HIST2H2BE could facilitate the dysfunction of metabolism-related progression through the dysregulations of the WNT and the MAPK signaling pathways resulting in NAFLD&NASH. The accumulated epigenetic modifications and dysregulations of miR-21 could facilitate the dysfunctions of metabolism-related, apoptosis-related, and DNA repair-related progression through dysregulations of the WNT and the MAPK signaling pathways resulting in HCC. Dysregulation of miR-21 and miR-122 could contribute to tumor invasion and metastasis to facilitate further aggressive tumor progression.
Figure 7
Figure 7
Progression mechanisms for the pathogenesis of PBC&PSC and the hepatocarcinogenesis through PBC&PSC. The blue, red, green, and yellow lines represent the interactions (or regulations) in PBC&PSC pathogenesis, PBC&PSC hepatocarcinogenesis, the hepatocarcinogenesis of normal liver through PBC&PSC, and the aggressive tumor progression, respectively, based on Figures 3 and 4. The epigenetic modifications of HIST2H2BE and RPL23A could facilitate the dysfunction of autoimmune-related progression through dysregulations of the WNT and the MAPK signaling pathways resulting in PBC&PSC. The accumulated epigenetic modifications and the dysregulation of miR-29a, miR-122, and miR-21 could facilitate the dysfunction of metabolism-related, apoptosis-related, autoimmune-related and DNA repair-related progression through the dysregulation of the WNT and the MAPK signaling pathways resulting in HCC. Dysregulation of miR-21, miR-122, and miR-29a could contribute to tumor invasion and metastasis to facilitate further aggressive tumor progression.
Figure 8
Figure 8
Schematic structure of the pathogenic and hepatocarcinogenic mechanisms of NAFLD&NASH and PBC&PSC.

Similar articles

See all similar articles

Cited by 2 articles

References

    1. Bandiera S., Pfeffer S., Baumert T. F., Zeisel M. B. miR-122--a key factor and therapeutic target in liver disease. Journal of Hepatology. 2015;62(2):448–457. doi: 10.1016/j.jhep.2014.10.004. - DOI - PubMed
    1. Nishikawa H., Osaki Y. Non-B, non-C hepatocellular carcinoma. International Journal of Oncology. 2013;43(5):1333–1342. doi: 10.3892/ijo.2013.2061. - DOI - PubMed
    1. Nishikawa H., Arimoto A., Wakasa T., Kita R., Kimura T., Osaki Y. Comparison of clinical characteristics and survival after surgery in patients with non-B and non-C hepatocellular carcinoma and hepatitis virus-related hepatocellular carcinoma. Journal of Cancer. 2013;4(6):502–513. doi: 10.7150/jca.6503. - DOI - PMC - PubMed
    1. El-Haggar S. M., Mostafa T. M. Comparative clinical study between the effect of fenofibrate alone and its combination with pentoxifylline on biochemical parameters and liver stiffness in patients with non-alcoholic fatty liver disease. Hepatology International. 2015;9(3):471–479. doi: 10.1007/s12072-015-9633-1. - DOI - PubMed
    1. Pollheimer M. J., Fickert P. Animal models in primary biliary cirrhosis and primary sclerosing cholangitis. Clinical Reviews in Allergy & Immunology. 2015;48(2-3):207–217. doi: 10.1007/s12016-014-8442-y. - DOI - PubMed

MeSH terms

Substances

Feedback