A Comprehensive Analysis of the Dynamic Biological Networks in HCV Induced Hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, which is closely related to hepatitis C and cirrhosis. The molecular mechanisms underlying the hepatocarcinogenesis induced by HCV infection remain clarified from a standpoint of systems biology. By integrating data from protein-protein interactions, transcriptional regulation, and disease related microarray analysis, we carried out a dynamic biological network analysis on the progression of HCV induced hepatocarcinogenesis, and systematically explored the potentially disease-related mechanisms through a network view. The dysfunctional interactions among proteins and deregulatory relationships between transcription factors and their target genes could be causes for the occurrence and progression of this disease. The six pathologically defined disease stages in the development and progression of HCC after HCV infection were included in this study. We constructed disease-related biological networks for each disease stage, and identified progression-related sub-networks that potentially play roles in the developmental stage of the corresponding disease and participate in the later stage of cancer progression. In addition, we identified novel risk factors related to HCC based on the analysis of the progression-related sub-networks. The dynamic characteristics of the network reflect important features of the disease development and progression, which provide important information for us to further explore underlying mechanisms of the disease

Functional and Topological Properties in Hepatocellular Carcinoma Transcriptome

Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality. However, little is known about the precise molecular mechanisms involved in tumor formation and pathogenesis. The primary goal of this study was to elucidate genome-wide molecular networks involved in development of HCC with multiple etiologies by exploring high quality microarray data. We undertook a comparative network analysis across 264 human microarray profiles monitoring transcript changes in healthy liver, liver cirrhosis, and HCC with viral and alcoholic etiologies. Gene co-expression profiling was used to derive a consensus gene relevance network of HCC progression that consisted of 798 genes and 2,012 links. The HCC interactome was further confirmed to be phenotype-specific and non-random. Additionally, we confirmed that co-expressed genes are more likely to share biological function, but not sub-cellular localization. Analysis of individual HCC genes revealed that they are topologically central in a human protein-protein interaction network. We used quantitative RT-PCR in a cohort of normal liver tissue (n = 8), hepatitis C virus (HCV)-induced chronic liver disease (n = 9), and HCC (n = 7) to validate co-expressions of several well-connected genes, namely ASPM, CDKN3, NEK2, RACGAP1, and TOP2A. We show that HCC is a heterogeneous disorder, underpinned by complex cross talk between immune response, cell cycle, and mRNA translation pathways. Our work provides a systems-wide resource for deeper understanding of molecular mechanisms in HCC progression and may be used further to define novel targets for efficient treatment or diagnosis of this disease

Transcriptional regulatory networks in Hepatitis C virus_induced hepatocellular carcinoma

HCV is an epidemic affecting an estimated 160 million individuals worldwide or approximately 2.35% of the world’s population.(1) This is partly because HCV exhibits high genetic variation which thereby characterizes each region with its own genetic prevalence. Therefore, understanding the transcriptional regulatory elements that influence the progression of liver disease in the presence of HCV infection is thereby crucial for diagnostic and therapeutic purposes. Systems biology provides a road map by which these elements may be easily identified. In this study 124 microarray samples were assessed in order to determine differentially expressed genes for 4 tissue types/conditions (normal, cirrhosis, cirrhosis HCC, and HCC). Differentially expressed genes were assessed for their functional clustering and those genes were annotated with their potential transcription factors and miRNAs. Transcriptional regulatory networks were constructed to visualize each pairwise comparison between the 4 tissue types/conditions. In this study that 12 transcription factors were found to have high expression patterns amongst all 6 pairwise comparisons and these transcription factors also provide insight the conditions of the liver as it progresses through hepatic cirrhosis, hepatic steatosis, and the induction of cancer. With the plethora of miRNAs that are found in the liver, each liver condition was found to have its own signature miRNA expression pattern. In the 6 pairwise comparisons 14 miRNAs were found to have high expression patterns in all 6 pairwise comparisons and their regulation in HCC was determined as well as their impact on cellular homeostasis. Based on the findings of this study and a systematic analysis of many studies it can be concluded that as the liver progresses from cirrhosis to steatosis and eventually becoming carcinomic there are specific transcription factors regulating this transition through each stage. Whereas the condition of the liver digresses, the down-regulation of miRNAs’ expression makes the transition of the liver through each pathological stage more apparent. Therefore, an understanding of the transcriptional regulatory attributes acts as a road map to provide interference strategies in order to target the stages in the progression of HCV induced HCC

Molecular mechanisms involved in HCC recurrence after direct-acting antiviral therapy

Chronic hepatitis C is associated with a high risk of developing hepatocellular carcinoma (HCC) because of a direct effect of the Hepatitis C Virus (HCV) proteins and an indirect oncogenic effect of chronic inflammation and impaired immune response. The treatment of chronic hepatitis C markedly reduces all-cause mortality; in fact, interferon-based treatment has shown a reduction of HCC incidence of more than 70%. The recent introduction of the highly effective direct-acting antivirals (DAAs) has completely changed the scenario of chronic hepatitis C (CHC) with rates of HCV cure over 90%. However, an unexpectedly high incidence of HCC recurrence was observed in patients after DAA treatment (27% versus 0.4–2% in patients who received interferon treatment). The mechanism that underlies the high rate of tumor relapse is currently unknown and is one of the main issues in hepatology. We reviewed the possible mechanisms involved in HCC recurrence after DAA treatment

Molecular mechanisms of hepatitis C virus–induced hepatocellular carcinoma

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Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) represents one of the most significant global health issues, given its high prevalence and the challenging nature and physiology of the liver and hepatic surgery, in its many forms. This means that the most appropriate management for HCC should incorporate a multidisciplinary approach, combining the expertise from several different specialties. This book showcases the various steps in the development, diagnosis, staging, and management of HCC and provides views and thoughts from true experts in the field. As such, it is a useful resource for any physician or surgeon, whether training or practicing, who is interested in caring for patients with HCC