scholarly journals Identification of Key Regulators of Hepatitis C Virus-Induced Hepatocellular Carcinoma by Integrating Whole-Genome and Transcriptome Sequencing Data

2021 ◽  
Vol 12 ◽  
Author(s):  
Guolin Chen ◽  
Wei Zhang ◽  
Yiran Ben

Background: Hepatitis C virus (HCV) infection is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Despite recent advances in the understanding of the biological basis of HCC development, the molecular mechanisms underlying HCV-induced HCC (HCC-HCV) remain unclear. The carcinogenic potential of HCV varies according to the genotype and mutation in its viral sequence. Moreover, regulatory pathways play important roles in many pathogenic processes. Therefore, identifying the pathways by which HCV induces HCC may enable improved HCC diagnosis and treatment.Methods: We employed a systematic approach to identify an important regulatory module in the process of HCV-HCC development to find the important regulators. First, an HCV-related HCC subnetwork was constructed based on the gene expression in HCC-HCV patients and HCC patients. A priority algorithm was then used to extract the module from the subnetworks, and all the regulatory relationships of the core genes of the network were extracted. Integrating the significantly highly mutated genes involved in the HCC-HCV patients, core regulatory modules and key regulators related to disease prognosis and progression were identified.Result: The key regulatory genes including EXO1, VCAN, KIT, and hsa-miR-200c-5p were found to play vital roles in HCV-HCC development. Based on the statistics analysis, EXO1, VCAN, and KIT mutations are potential biomarkers for HCV–HCC prognosis at the genomic level, whereas has-miR-200c-5P is a potential biomarker for HCV–HCC prognosis at the expression level.Conclusion: We identified three significantly mutated genes and one differentially expressed miRNA, all related to HCC prognosis. As potential pathogenic factors of HCC, these genes and the miRNA could be new biomarkers for HCV-HCC diagnosis.

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Trina Das ◽  
Deborah L. Diamond ◽  
Matthew Yeh ◽  
Sajida Hassan ◽  
Janine T. Bryan ◽  
...  

Chronic hepatitis C virus (HCV) induced hepatocellular carcinoma (HCC) is a primary indication for liver transplantation (LT). In western countries, the estimated rate of HCC recurrence following LT is between 15% and 20% and is a major cause of mortality. Currently, there is no standard method to treat patients who are at high risk for HCC recurrence. The aim of this study was to investigate the molecular signatures underlying HCC recurrence that may lead to future studies on gene regulation contributing to new therapeutic options. Two groups of patients were selected, one including patients with HCV who developed HCC recurrence (HCC-R) ≤3 years from LT and the second group including patients with HCV who did not have recurrent HCC (HCC-NR). Microarray analysis containing more than 29,000 known genes was performed on formalin-fixed-paraffin-embedded (FFPE) liver tissue from explanted livers. Gene expression profiling revealed 194 differentially regulated genes between the two groups. These genes belonged to cellular networks including cell cycle G1/S checkpoint regulators, RAN signaling, chronic myeloid leukemia signaling, molecular mechanisms of cancer, FXR/RXR activation and hepatic cholestasis. A subset of molecular signatures associated with HCC recurrence was found. The expression levels of these genes were validated by quantitative PCR analysis.


2012 ◽  
Vol 4 (12) ◽  
pp. 342 ◽  
Author(s):  
Denis Selimovic ◽  
Abdelouahid El-Khattouti ◽  
Hanan Ghozlan ◽  
Youssef Haikel ◽  
Ola Abdelkader ◽  
...  

2018 ◽  
Vol 115 (30) ◽  
pp. E7139-E7148 ◽  
Author(s):  
Ruian Ke ◽  
Hui Li ◽  
Shuyi Wang ◽  
Wenge Ding ◽  
Ruy M. Ribeiro ◽  
...  

RNA viruses exist as a genetically diverse quasispecies with extraordinary ability to adapt to abrupt changes in the host environment. However, the molecular mechanisms that contribute to their rapid adaptation and persistence in vivo are not well studied. Here, we probe hepatitis C virus (HCV) persistence by analyzing clinical samples taken from subjects who were treated with a second-generation HCV protease inhibitor. Frequent longitudinal viral load determinations and large-scale single-genome sequence analyses revealed rapid antiviral resistance development, and surprisingly, dynamic turnover of dominant drug-resistant mutant populations long after treatment cessation. We fitted mathematical models to both the viral load and the viral sequencing data, and the results provided strong support for the critical roles that superinfection and cure of infected cells play in facilitating the rapid turnover and persistence of viral populations. More broadly, our results highlight the importance of considering viral dynamics and competition at the intracellular level in understanding rapid viral adaptation. Thus, we propose a theoretical framework integrating viral and molecular mechanisms to explain rapid viral evolution, resistance, and persistence despite antiviral treatment and host immune responses.


2019 ◽  
Vol 31 (2) ◽  
pp. 214
Author(s):  
AhmedE Zeid ◽  
AhmedM El-Gohary ◽  
MohamedE Ibrahim ◽  
FatmaI Dewedar ◽  
EssamA Elzoheiry

2016 ◽  
Vol 22 (10) ◽  
pp. 853-861 ◽  
Author(s):  
T. Vescovo ◽  
G. Refolo ◽  
G. Vitagliano ◽  
G.M. Fimia ◽  
M. Piacentini

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Yinan Zheng ◽  
Ryan A. Hlady ◽  
Brian T. Joyce ◽  
Keith D. Robertson ◽  
Chunyan He ◽  
...  

Abstract Background The two most common repetitive elements (REs) in humans, long interspersed nuclear element-1 (LINE-1) and Alu element (Alu), have been linked to various cancers. Hepatitis C virus (HCV) may cause hepatocellular carcinoma (HCC) by suppressing host defenses, through DNA methylation that controls the mobilization of REs. We aimed to investigate the role of RE methylation in HCV-induced HCC (HCV-HCC). Results We studied methylation of over 30,000 locus-specific REs across the genome in HCC, cirrhotic, and healthy liver tissues obtained by surgical resection. Relative to normal liver tissue, we observed the largest number of differentially methylated REs in HCV-HCC followed by alcohol-induced HCC (EtOH-HCC). After excluding EtOH-HCC-associated RE methylation (FDR < 0.001) and those unable to be validated in The Cancer Genome Atlas (TCGA), we identified 13 hypomethylated REs (11 LINE-1 and 2 Alu) and 2 hypermethylated REs (1 LINE-1 and 1 Alu) in HCV-HCC (FDR < 0.001). A majority of these REs were located in non-coding regions, preferentially enriched with chromatin repressive marks H3K27me3, and positively associated with gene expression (median correlation r = 0.32 across REs). We further constructed an HCV-HCC RE methylation score that distinguished HCV-HCC (lowest score), HCV-cirrhosis, and normal liver (highest score) in a dose-responsive manner (p for trend < 0.001). HCV-cirrhosis had a lower score than EtOH-cirrhosis (p = 0.038) and HCV-HCC had a lower score than EtOH-HCC in TCGA (p = 0.024). Conclusions Our findings indicate that HCV infection is associated with loss of DNA methylation in specific REs, which could implicate molecular mechanisms in liver cancer development. If our findings are validated in larger sample sizes, methylation of these REs may be useful as an early detection biomarker for HCV-HCC and/or a target for prevention of HCC in HCV-positive individuals.


2009 ◽  
Vol 45 (4) ◽  
pp. 459-467 ◽  
Author(s):  
Shuji Kanmura ◽  
Hirofumi Uto ◽  
Yuko Sato ◽  
Koutarou Kumagai ◽  
Fumisato Sasaki ◽  
...  

2012 ◽  
Vol 421 (4) ◽  
pp. 837-843 ◽  
Author(s):  
Fumio Nomura ◽  
Kazuyuki Sogawa ◽  
Kenta Noda ◽  
Masanori Seimiya ◽  
Kazuyuki Matsushita ◽  
...  

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