title: How Hepatitis C Virus Leads to Hepatocellular Carcinoma: A Network-Based Study.
abstract: BACKGROUND
  Hepatitis C virus (HCV) has been known as a major cause of hepatocellular carcinoma (HCC) worldwide. However, the distinct molecular mechanisms underlying the effects of HCV proteins on the HCC progression have remained unclear.
  
  
  OBJECTIVE
  In the present study, we studied the possible role of HCV in the HCC initiation and invasion using topological analysis of protein-protein interaction (PPI) networks.
  
  
  METHODS
  After analysis with GEO2R, a PPI network of differentially expressed genes (DEGs) was constructed for both chronic HCV and HCC samples. The STRING and GeneMANIA databases were used to determine the putative interactions between DEGs. In parallel, the functional annotation of DEGs was performed using g: Profiler web tool. The topological analysis and network visualization was carried outperformed using Cytoscape software and the top hub genes were identified. We determined the hub genes-related miRNAs using miRTarBase server and reconstructed a miRNA-Hubgene network.
  
  
  RESULTS
  Based on the topological analysis of miRNA-Hubgene network, we identified the key hub miRNAs. In order to identify the most important common sub-network, we aligned two PPI networks using NETAL tool. The c-Jun gene was identified as the most important hub gene in both HCV and HCC networks. Furthermore, the hsa-miR-34a, hsa-miR-155, hsa-miR-24, hsa-miR-744 and hsa-miR-92a were recognized as the most important hub miRNAs with positive correlation in the chronic HCV and HCC samples. Functional annotation of differentially expressed miRNAs (DEMs) using the tool for annotations of human miRNAs (TAM) revealed that there is a considerable overlap between miRNA gene expression profiles of HCV-infected and HCC cells.
  
  
  CONCLUSIONS
  Our results revealed the possible crucial genes and miRNAs involved in the initiation and progression of HCC cells infected with HCV.
authors.affiliation: Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran.
authors.forename: Vahdat
authors.initials: V
authors.lastname: Poortahmasebi
authors.affiliation: Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, IR Iran.
authors.forename: Mansour
authors.initials: M
authors.lastname: Poorebrahim
authors.affiliation: Department of Microbiology, Tonekabon Branch, Islamic Azad University, Tonekabon, IR Iran.
authors.forename: Saeideh
authors.initials: S
authors.lastname: Najafi
authors.affiliation: Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran.
authors.forename: Seyed Mohammad
authors.initials: SM
authors.lastname: Jazayeri
authors.affiliation: Middle East Liver Diseases (MELD) Center, Tehran, IR Iran.
authors.forename: Seyed Moayed
authors.initials: SM
authors.lastname: Alavian
authors.affiliation: Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, IR Iran.
authors.forename: Seyed Shahriar
authors.initials: SS
authors.lastname: Arab
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada.
authors.forename: Saeid
authors.initials: S
authors.lastname: Ghavami
authors.affiliation: Middle East Liver Diseases (MELD) Center, Tehran, IR Iran.
authors.forename: Seyed Ehsan
authors.initials: SE
authors.lastname: Alavian
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada.
authors.forename: Adel
authors.initials: A
authors.lastname: Rezaei Moghadam
authors.affiliation: Department of Cell Biology and Anatomy, Schulich School of Medicine and Dentistry, Western University, London, Canada.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Amiri
keywords: HCC; HCV; PPI Networks; Topological Analysis; miRNA