Hepatitis C Virus Protein Interaction Network Analysis Based on Hepatocellular Carcinoma

Abstract

Epidemiological studies have validated the association between hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC). An increasing number of studies show that protein-protein interactions (PPIs) between HCV proteins and host proteins play a vital role in infection and mediate HCC progression. In this work, we collected all published interaction between HCV and human proteins, which include 455 unique human proteins participating in 524 HCV-human interactions. Then, we construct the HCV-human and HCV-HCC protein interaction networks, which display the biological knowledge regarding the mechanism of HCV pathogenesis, particularly with respect to pathogenesis of HCC. Through in-depth analysis of the HCV-HCC interaction network, we found that interactors are enriched in the JAK/STAT, p53, MAPK, TNF, Wnt, and cell cycle pathways. Using a random walk with restart algorithm, we predicted the importance of each protein in the HCV-HCC network and found that AKT1 may play a key role in the HCC progression. Moreover, we found that NS5A promotes HCC cells proliferation and metastasis by activating AKT/GSK3β/β-catenin pathway. This work provides a basis for a detailed map tracking new cellular interactions of HCV and identifying potential targets for HCV-related hepatocellular carcinoma treatment.

Hepatitis C Virus Regulates its Replication by Maturing miR-122 Through Akt-Dependent Phosphorylation of KSRP

“…We also demonstrate that Akt phosphorylation of S193-KSRP is pivotal for this function (Figures 1D Our results showing that HCV-induced maturation of miR-122 is mediated by KSRP as a result of Akt activation via its phosphorylation at serine residue 473 is in keeping with previous observations of the activation of PI3K/Akt signaling pathway during HCV infection (Z. Liu et al, 2012). Accumulating evidence suggests that the NS5A protein, alone or in association with other non-structural viral proteins, plays an important role in HCV-induced Akt activation (Cheng et al, 2015;Han et al, 2016;Higgs et al, 2013;Shi, Hoffman, & Liu, 2016). Altogether, our results show that, in addition to its many reported effects in HCV-infected cells, HCV-induced Akt activation plays a key role in the viral lifecycle by regulating replication through miR-122 maturation.…”

“…The Akt-dependent phosphorylation of KSRP at serine 193 promotes nuclear pri-miRNA processing in the context of reduced AREcontaining mRNA degradation (Briata et al, 2013;Briata et al, 2005;Y. Liu & Liu, 2011;Zhang, Wan, Berger, He, & Lu, 2011). HCV, particularly its non-structural 5A (NS5A) protein, has been shown to activate the phosphatidylinositol-3-kinase (PI3K) signaling pathway in many models, thereby activating its downstream effector, the serine/threonine kinase Akt (Bose, Meyer, Di Bisceglie, Ray, & Ray, 2012;Cheng et al, 2015;Han, Niu, Wang, & Li, 2016;He et al, 2002;Higgs, Lerat, & Pawlotsky, 2013;Milward, Mankouri, & Harris, 2010;Street, Macdonald, Crowder, & Harris, 2004). Here, we demonstrate that HCV infection induces KSRP phosphorylation at serine position 193 through Akt activation and that this P-S193-KSRP in turn induces the maturation of miR-122, which favors viral replication.…”

Oncogenic Wnt3a: a promising specific biomarker in hepatocellular carcinoma

“…Epidemiological studies have validated the association between HCV infection and HCC. An increasing number of studies show that protein-protein interactions between HCV proteins and host proteins play a vital role in infection and mediate HCC progression [50] . The role of nonstructural (NS5A) protein of HCV in vivo has been accentuated in induction of this pathway mainly to the canonical pathway.…”

“…Wnt3a [19] (> 800 ng/L) AFP [19] (> 50 ng/mL) HS-GGT [17] (> 5.5 U/L) GPC-3 [67] (positive) Wnt3a [19] + AFP Sensitivity (%) 92. 50…”

The risk of hepatocellular carcinoma after sustained virological response in patients treated with the new direct-acting antiviral drugs: should we be worry about it?

“…Moreover, the molecular mechanisms involved in HCC development are not fully understood [14]. Some mechanisms are due to HCV because multiple important viral proteins may play a role in carcinogenesis [32][33][34]. Others could be due to indirect reasons.…”