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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review

Tatsuo Kanda, Taichiro Goto, Yosuke Hirotsu and 2 more

International Journal of Molecular Sciences · 2019 · Review · CC BY

doi:10.3390/ijms20061358

Abstract

Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, have liver cirrhosis, the severity of which can prevent effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Because most patients with liver cirrhosis are asymptomatic, it is difficult to diagnose early stages of HCC, and patients with hepatic symptoms and HCC are considered to have advanced-stage HCC. These issues explain the prevalence of poor prognosis for HCC patients.

HCC is the 4th most common neoplasm and the 2nd commonest cause of cancer deaths in the world. Notably, HCC is a male-dominant disease, with the incidence of HCC ~3-fold higher in males than in females. Hepatitis B virus (HBV) infection is associated with the higher HCC incidence in persons with cirrhosis, occurring in high endemic areas and in Western countries (5-year cumulative incidence, 15% and 10%, respectively). In hepatitis C virus (HCV)-related cirrhosis, the 5-year cumulative HCC risk is 30% in Japan and 17% in Western countries.

Histologically, liver fibrosis involves the deposition of extracellular matrix proteins, including collagen, in higher-order structures within hepatic parenchyma, with hepatic stellate cells and fibroblasts representing major producers of collagen. The histological pattern of liver fibrosis is not unique, and the extent and distribution of liver fibrosis exhibits various patterns depending on different etiologies. Excessive liver fibrosis often develops within portal tracts and extends into the hepatic parenchyma in viral hepatitis, with these activities appearing to be associated with persistent portal inflammation. Bridging fibrosis appears following the development of periportal fibrosis and extends across lobules to connect mesenchymal structures (portal tracts and central veins) to different extents. Generally, these processes accompany intrahepatic portosystemic vascular shunting and regeneration of hepatocytes, thereby transforming from normal hepatic architecture to nodule formation and finally establishing the structure of cirrhosis.

In this review, we discuss the molecular mechanisms underlying the progression of liver cirrhosis to HCC. We expect that this review will help clinicians diagnose and treat patients with liver cirrhosis and/or HCC in their daily clinical practice. Notably, ~70% of HCC patients are afflicted with HBV or HCV infection; therefore, we focused on the occurrence of HCC during HBV and HCV infection (Figure 1).

2.1. Development of Liver Cirrhosis in Patients with Chronic Hepatitis B Infection

HBV infection causes acute and chronic hepatitis, cirrhosis, and HCC. HBV-carrier rates are higher in African and Asian countries and globally are estimated to have resulted in 786,000 deaths in 2010, the majority of which were attributed to HCC (341,400 deaths) and cirrhosis (312,400 deaths). Annual rates of development from chronic hepatitis B to liver cirrhosis ranged from 2.1 to 6.0%, and annual rates of the development of liver cirrhosis in HBV e antigen (HBeAg)-positive or anti-HBe-positive patients were 2.4% and 1.3%, respectively.

HBeAg-positivity and elevated HBV DNA levels are risk factors for the development of liver cirrhosis in patients with chronic hepatitis B. Sumi et al. reported that progression to cirrhosis is slower in HBV genotype B than that in HBV genotype C infection. Additionally, for patients with chronic hepatitis B infection, coinfection with HCV or human immunodeficiency virus (HIV) is another risk factor for the development of liver cirrhosis.

Older age (≥55 years), male gender, chronic active hepatitis, higher alanine aminotransferase (ALT) levels, history of decompensation, ferredoxin-1-associated single-nucleotide polymorphism, HLA-DQA2 rs9276370 variants, and HLA-DQB2 rs7756516 variants are also respective risk factors for the development of liver cirrhosis.

2.2. Development of HCC in Patients with HBV-related Liver Cirrhosis

Annual rates of occurrence of HCC in patients with HBV-related cirrhosis are ~2.3%. Higher HBV DNA levels, HBeAg-positivity, higher HBV surface antigen (HBsAg) levels, HBV genotype C, and basal core-promoter mutations are viral risk factors for the occurrence of HCC, and older age, male gender, chronic active hepatitis, higher ALT levels, and higher α-fetoprotein levels are non-viral risk factors for the occurrence of HCC. Treatment with nucleos(t)ide analogs for HBV control decreases the occurrence rates of HCC in patients with HBV-related cirrhosis.

3. Liver Cirrhosis and Its Progression to HCC with HCV Infection

HCV infection causes acute and chronic hepatitis, cirrhosis, and HCC. In 2015, there were 170,000 new HCV infections, with annual incidence rates of cirrhosis accompanying HCV infection at 1.1%. Forns et al. reported that chronic HCV infection displayed a high rate of progression to liver cirrhosis over a prolonged follow-up period, and that an aspartate aminotransferase (AST) value >70 IU/L was associated with cirrhosis development [odds ratio (OR): 4.22, 95% confidence interval (CI): 1.3–13.8]. Additionally, there is an association between HCV genotype 3 and steatosis, which accelerates fibrosis development over time in HCV genotype 3-infected patients. Moreover, previous studies reported that exposure to HCV at a young age is associated with a reduced rate of fibrosis progression, and that liver fibrosis progression was mainly dependent on the age and duration of infection. The evidences are growing that liver steatosis and diabetes mellitus are factors affecting progression to HCC in HCV-infected patients with compensated cirrhosis. These comorbidities typically affecting aged patients might explain the increased malignant progression of the cirrhotic liver damage. Ongoing alcohol consumption and severe inflammation according to liver histology are also associated with liver fibrosis progression. A multivariate analysis of HCV-infected patients revealed that only male sex (OR: 3.17, 95% CI: 1.152–8.773) and HIV infection (OR: 6.85, 95% CI: 2.93–16.005) were associated with advanced liver fibrosis. Furthermore, HBsAg-positive HCV-coinfected patients are at high risk of developing liver disease, and injected-drug users; patients with insulin resistance or diabetes; and patients with concurrent obesity, diabetes, and steatosis are also at risk of advanced liver fibrosis. Following antiviral treatment, sustained virological response (SVR) can reduce liver fibrosis progression in most patients infected with HCV.

Annual rates of HCC occurrence in patients with HCV-related cirrhosis are ~4.5%. Caporaso et al. found that mean age and male/female ratio were significantly higher in patients with HCC plus liver cirrhosis than in those with liver cirrhosis alone. Additionally, HBsAg-positive HCV-coinfected patients with liver cirrhosis are at a high risk of developing HCC, with elevated ALT levels and hepatic steatosis risk factors for the development of HCC in patients with HCV-related liver cirrhosis. SVR can reduce HCC development in most patients infected with HCV-related liver cirrhosis, although changes in the risk of HCC development following HCV eradication with direct-acting antivirals (DAAs) is controversial. Further studies will be needed in DAA-era.

4. Molecular Mechanisms of Liver Cirrhosis and Its Progression to HCC

Accumulation of genetic mutations occurs during HCC progression. Recent advances in next-generation sequencing technology to augment Sanger sequencing enabled whole-genome sequencing to allow critical insights into the molecular mechanisms associated with this activity.

4.1. Driver-Gene Candidates in HCC

Totoki et al. found 30 candidate driver genes [telomerase reverse transcriptase (TERT), catenin β1 (CTNNB1), tumor protein p53 (TP53), AT-rich interaction domain 2 (ARID2), axin 1 (AXIN1), TSC complex subunit 2 (TSC2), retinoblastoma protein 1 (RB1), activin A receptor type 2A (ACVR2A), bromodomain containing 7 (BRD7), cyclin dependent kinase inhibitor (CDKN)1A, menin 1 (MEN1), polypeptide N-acetylgalactosaminyltransferase 11 (GALN11), fibroblast growth factor 19 (FGF19), cyclin (CCN)D1, AT-rich interaction domain 1A (ARID1A), CDKN2A, CDKN2B, ribosomal protein S6 kinase, 90 kDa, polypeptide 3 (RPS6KA3), nuclear factor, erythroid 2 like 2 (NFE2L2), nuclear receptor corepressor 1 (NCOR1), alcohol dehydrogenase 1B, β polypeptide (ADH1B), Snf2-related CREB binding protein (CREBBP) activator protein (SRCAP), Fc receptor like 1 (FCRL1), phosphatase and tensin homolog (PTEN), heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), cytochrome P450 family 2 subfamily E member 1 (CYP2E1), mitogen-activated protein kinase 3 (MAP2K3), tuberous sclerosis (TSC)1, transmembrane protein 99 (TMEM99), and glucose-6-phosphatase, catalytic subunit (G6PC)] and 11 core pathway modules [β-catenin, chromatin remodeling, DNA repair, estrogen-related receptor beta (ERRB), fibrinogen, mechanistic target of rapamycin kinase (mTOR), synaptic connection, TERT, p53, NOTCH, and NCOR] through the collection of data from 503 HCC genomes from different populations (Table 1).

Fujimoto et al. identified 15 significantly mutated genes, including TP53, ERBB-receptor feedback inhibitor 1, Zic family member 3, CTNNB1, glucoside xylosyltransferase 1, otopetrin 1, albumin (ALB), ATM serine/threonine kinase (ATM), zinc finger protein 226, ubiquitin specific peptidase (USP)25, WW-domain-containing E3 ubiquitin protein ligase 1, immunoglobulin superfamily member 10, ARID1A, ubiquitin protein ligase E3 component n-recognin 3, and bromodomain adjacent to zinc finger domain 2B, after sequencing and analyzing the whole genomes of 27 HCCs, including 25 with HBV- or HCV-associated HCC. Additionally, whole-genome sequencing analyses of HCCs demonstrated the influence of etiological backgrounds on mutation patterns and recurrent mutations in chromatin regulators. The authors found that multiple chromatin regulators, including ARID1A, ARID1B, ARID2, lysine methyltransferase 2A, and lysine methyltransferase 2C, were mutated in ~50% of the tumors, with clonal integration of the HBV genome in the TERT gene frequently detected.

4.2. The p53-RB Pathway

TP53 mutations have been reported in HCC in Japan and aflatoxin B1-induced HCC. In HCC, the p53-RB pathway is altered in 72% of cases, with 68% of these a result of significantly altered genes. Somatic mutations and copy number alterations in TP53, which plays a central role in apoptosis, are present in 31% and 37% of cases, respectively. Among the upstream genes targeted by p53, somatic mutations and copy number alterations in ATM are present in 4% and 6% of cases, respectively; those in RPS6KA3 are present in 4% and 5% of cases, respectively, and those in CDKN2A are present in 2% and 20% of cases, respectively. Among downstream genes targeted by p53, somatic mutations and copy number alterations in CDKN1A are present in 1% and 1% of cases, respectively; those in FBXW7 are present in <1% and 16% of cases, respectively, and those in CCNE1, which suppress RB1 transcription and promote cell cycle progression, are present in 0% and 2% of cases, respectively. Among upstream genes targeted by RB, somatic mutations and copy number alterations in CCND1 are present in 0% and 8% of cases, respectively. Somatic mutations and copy number alterations in RB1, which inhibit cell cycle progression, are present in 4% and 20% of cases, respectively. Additionally, RB controls the levels of p21, which is associated with hepatocarcinogenesis. Overall, 72% of HCC cases harbor alterations in component genes of either the p53 or RB pathway alone or the combined p53-RB pathway (Figure 2).

4.3. The β-catenin Pathway (WNT Pathway)

In HCC, the β-catenin pathway is altered in 66% of cases, with 51% of these involving significantly altered genes. Somatic mutations and copy number alterations in CTNNB1, which induce the expression of WNT target genes and transcription of CCND1 resulting in inhibited RB1 expression, are present in 31% and <1% of cases, respectively. Among the upstream genes targeted by β-catenin, somatic mutations and copy number alterations in NCOR1 are present in 2% and 29% of cases, respectively; those in FGF19 are present in 0% and 6% of cases, respectively; those in AXIN1 are present in 6% and 15% of cases, respectively; and those in APC are present in 2% and 4% of cases, respectively. Overall, 66% of HCC cases harbored WNT-pathway-related alterations.

4.4. Chromatin and Transcription Modulators

In HCC, chromatin-remodeling pathways are altered in 67% of cases, with 41% of these involving significantly altered genes. Among upstream genes associated with the nucleosome-remodeling pathway, somatic mutations and copy number alterations in ARID1B are present in <1% and 15% of cases, respectively; those in ARID1A are present in 8% and 17% of cases, respectively; those in BRD7 are present in 2% and 16% of cases, respectively; those in ARID2 are present in 10% and 2% of cases, respectively; those in switch/sucrose non-fermentable (SWI/SNF)-related, matrix associated, actin-dependent regulator of chromatin (SMARC) subfamily C member 1 are present in <1% and 4% of cases, respectively; those in SMARC subfamily B member 1 are present in <1% and 6% of cases, respectively; those in SMARC subfamily A member 4 are present in 1% and 10%, respectively; those in SMARC subfamily E member 1 are present in <1% and 3% of cases, respectively; and those in SMARC subfamily A member 2 are present in 2% and 10% of cases, respectively. Additionally, Li et al. reported that 18.2% of patients with HCV-associated HCC in the United States and Europe harbored ARID2-inactivation mutations. Moreover, another study reported ARID1A mutation in 14 of 110 (13%) HBV-associated HCC specimens. ARID1A functions as the epigenetic regulation of hepatic lipid homeostasis, and its suppression leads to nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH).

Among upstream genes associated with the histone-modification pathway, somatic mutations and copy number alterations in NCOR1 are present in 2% and 29% of cases, respectively; those in SRCAP are present in 3% and 10% of cases, respectively; those in SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) are present in 2% and <1% of cases, respectively; and those in lysine demethylase 6A (KDM6A) are present in 1% and 5% of cases, respectively. Notably, the histone methyltransferase SETDB1 promotes HCC metastasis, and KDM6A is associated with the epithelial–mesenchymal transition in HCC.

4.5. Other Pathways

In HCC, the phosphoinositide 3-kinase (PI3K)–mTOR pathway is altered in 45% of cases, with 26% of these involving significantly altered genes. Somatic mutations and copy number alterations of PI3KCA (encoding the p110α subunit of PI3K) are present in 1% and <1% of cases, respectively; those in neurofibromin 1 are present in 4% and 3% of cases, respectively; those in PTEN are present in 1% and 10% of cases, respectively; those in inositol polyphosphate-4-phosphatase, type IIB, are present in 1% and 16% of cases, respectively; those in serine/threonine kinase 11 are present in <1% and 11% of cases, respectively; those in TSC1 are present in 2% and 8% of cases, respectively; and those in TSC2 are present in 5% and 14% of cases, respectively. TSC1 and TSC2 suppress mTOR expression, which promotes HCC proliferation and survival. In sorafenib-treated patients with HCC, oncogenic PI3K–mTOR-pathway alterations are associated with lower disease-control rates and decreased median progression-free survival and overall survival.

In HCC, the nuclear factor (erythroid-derived 2)-like 2 (NRF2)–kelch-like ECH-associated protein 1 (KEAP1) pathway is altered in 19% of cases, with 5% of these involving significantly altered genes. The NRF2–KEAP1 pathway is associated with an oxidative-stress response, and persistent activation of NRF2 through the accumulation of p62 is involved in HCC development.

There are many protein-coding genes recurrently mutated at a frequency of <5% in HCC, whereas HBV integrations and frequent noncoding mutations in the TERT promoter represent prominent examples of noncoding mutations in HCC. Nault et al. identified frequent somatic mutations resulting in the activation of the TERT promoter in HCC (59%), cirrhotic preneoplastic macronodules (25%), and hepatocellular adenomas with malignant transformation in HCC (44%). Moreover, TERT-promoter mutation represents the most frequent genetic alteration in HCC arising from the cirrhotic or non-cirrhotic liver, resulting in reportedly enhanced TERT activity in HCC.

5.1. HBV Genome Integration Promotes HCC

The discovery that HBV integrates into host chromosomes calls into question whether HBV genome integration interacts with the activation of oncogenic processes in HCC. Tokino et al. could not detect specific HBV genome-integration sites in chromosomes. About half of HBV DNA-cell DNA junctions are located within the so-called cohesive end region that lies between two 11-bp direct repeats (DR1 and DR2) in the HBV genome where transcription and replication of the genome are initiated. All of the integrated HBV genomes were defective in at least one site around the cohesive end region, particularly within the HBx gene. Additionally, Imazeki et al. detected integrated HBV DNA in all nine HBsAg-seropositive HCCs and three of 25 (12%) HBsAg-seronegative HCCs in Japan. An analysis of breakpoints within the integration region showed that 40% of breakpoints were near the 1800th nucleotide of the HBV genome, which contains an enhancer, an HBx gene, and core promoters of the HBV genome.

TERT is located on chromosome 5p, which is one of the most common targets for amplification in non-small cell lung cancer and is reportedly directly associated with HBV genome integration. Recent data from whole-genome sequencing supports this observation and confirmed the frequent observation of HBV genome integration in the TERT locus in a high clonal proportion.

HBx expression might play a role in hepatocarcinogenesis by interfering with telomerase activity during hepatocyte proliferation, which is supported by breakpoint analysis of the HBV genome. HBx functions as a transcriptional activator and suppressor and has effects on hepatocellular apoptosis. HBx proteins may upregulate the transcriptional activation of human telomerase transcriptase. Cis-activation of human TERT mRNA by HBx gene may also be the mechanism in hepatocarcinogenesis.

Therefore, HBV genome integration into host genomes is a mechanism involved in HCC associated with HBV infection. Moreover, whole-genome sequencing demonstrated that the integration of HBV DNA into the host hepatocyte genome can be detected in 80% to 90% of HCC and in ~30% of non-HCC liver tissue adjacent to HCC, and that this integration appears prior to the occurrence of HCC. Thus, it is possible that occult HBV infection may also accelerate hepatocarcinogenesis in HBsAg-negative patients to some extent.

5.2. Inflammation Promotes HBV-Associated HCC

In general, a high number of HBV-DNA integrations randomly distributed among chromosomes has been detected in HBV-infected liver. Chronic HBV infection progresses through multiple phases, including immune tolerance, immune activation, immune control, and, in a subset of patients who achieve immune control and immune reactivation. Immune-mediated liver injury is often associated with elevated ALT levels, and elevations in tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β levels are often observed in the sera of HBV-infected patients. Additionally, long-lasting hepatic inflammation caused by host immune responses during chronic HBV infection can promote liver fibrosis, cirrhosis and HCC progression due to accelerated hepatocyte turnover rates and the accumulation of mutations.

5.3. Epigenetic Mechanisms Involved in HBV-Associated HCC

Epigenetic mechanisms play a role in HBV-associated hepatocarcinogenesis. MicroRNAs (miRs) are endogenous noncoding RNAs (18–22 nucleotides in length) that posttranscriptionally regulate the expression of target genes. miRs bind to the 3′-untranslated region (UTR) of target mRNA, thereby inhibiting translation.

Several miRNAs involved in the Toll-like receptor (TLR) signaling pathway play a critical role in innate immunity against HBV infection. For example, miR-145 and miR-148a target TLR3, miR-200b, miR-200c, miR148a, miR-455, and let-7-family members target TLR4, let-7b and miR-155 target TLR7, and miR-148a targets TLR9, and all of which are involved in HBV infection. HBV might influence miR expression and induce inflammatory cytokine production. Previous reports indicated that some hepatic miRs are involved in the pathogenesis of HBV-associated HCC, with certain serum miRs involved in HBV-associated HCC also potentially useful as biomarkers (Table 2).

Other noncoding RNAs, such as long noncoding RNAs (lncRNAs) and circular RNA (circRNA), are also involved in the pathogenesis of HBV-associated HCC. Functional studies reveal that lncRNAs (100–300 kb) contribute to the onset and progression of HBV-related HCC, and circRNAs, which form covalently closed continuous loops by means of unique non-canonical ‘head-to-tail’ splicing in the absence of free 3′ or 5′ ends, might promote the development of HBV-associated HCC.

Epigenetic silencing of genes, such as methylation of promoter regions, also regulates gene expression in HBV-associated HCC and could potentially serve as a diagnostic and prognostic marker of the disease. Additionally, HBV can cause epigenetic changes by altering the methylation state of cellular DNA, the posttranslational modification of histones, and miR expression, all of which are also critical for the pathogenesis of HBV-associated HCC.

5.4. Roles of HBV-encoded Proteins

HBV is a partially double-stranded DNA virus (genome length: 3200 bp) and a member of the Orthohepadnavirus genus and the Hepadnaviridae family. The HBV genome encodes at least four proteins [HBsAg, a core protein (splice variant: HBeAg), a DNA polymerase, and the HBx protein] that are translated from mRNAs transcribed from HBV covalently closed circular DNA and/or from HBV genome sequences integrated into the host genome. Viral protein translation is initiated through binding of the PreS2 domain of HBV surface antigens to protein kinase C (PKC)α/β, which triggers PKC-dependent activation of Raf-1 proto-oncogene serine/threonine kinase (RAF-1)/MAP2K signaling and transcription factors, such as activator protein-1 (AP-1) and nuclear factor kappaB (NF-kB), resulting in the increased proliferation of hepatocytes. PreS2-mediated activity subsequently upregulates the expression of the transcriptional coactivator with PDZ-binding motif by repressing miRNA-338-3p, which promotes HCC proliferation and migration. Moreover, a previous study showed that a truncated mutant of HBsAg increases HBV-related tumorigenesis in a mechanism potentially associated with the downregulated expression of tumor growth factor (TGF)BI associated with the TGFβ–SMAD pathway. Furthermore, HBsAg enhances the IL-6–STAT3 pathway, thereby increasing the HBsAg-mediated malignant potential of HBV-associated HCC.

The HBV core protein enhances cytokine production, and HBeAg is reportedly associated with the host immune response and cytokine production, both of which play roles in HBV-associated HCC.

Numerous studies reported an association between the HBx protein and hepatocarcinogenesis. Integrated HBV DNA harbors the conserved sequences for genes encoding the core protein, surface antigens, and HBx along with their respective promoter sequences, suggesting that HBx is important for hepatocarcinogenesis. HBx represents a transactivating factor, and transgenic mice expressing HBx develop HCC. HBx transactivates binding sites for the transcription factors AP-1 and NF-κB, activates the p53-RB and β-catenin pathways, and is involved in chromatin remodeling and transcriptional modulation in hepatocarcinogenesis.

Overexpression of the HBV polymerase due to core-gene deletion enhances HCC-cell growth by inhibiting miR-100. A previous study showed that transgenic mice expressing the reverse-transcriptase domain of HBV polymerase in their livers developed early cirrhosis with steatosis by 18 months of age, with 10% subsequently developing HCC.

6.1. Inflammation Promotes HCV-Associated HCC

Cytokines reflect the degree of inflammation in the liver of patients with chronic hepatitis C, with this production possibly related to HCC development. Takano et al. prospectively investigated the incidence of HCC in 124 cases with HCV infection, finding that HCC occurred in 13 cases that included 12 cirrhotic livers and only 1 non-cirrhotic liver and suggesting that most HCC occurs in advanced liver diseases in HCV-infected individuals. Because hepatic inflammation plays a role in the development of advanced liver diseases, inflammation is an important aspect in the development of HCC associated with chronic HCV infection.

6.2. Epigenetic Mechanisms Involved in HCV-Associated HCC

Epigenetic mechanisms also play a role in HCV-associated hepatocarcinogenesis. Previous studies reported the involvement of specific hepatic and serum miRs in the pathogenesis of HCV-associated HCC, with some of the serum miRs representing potentially useful biomarkers of the disease (Table 3). Notably, the number of reports of miRs involved in HCV-associated HCC is smaller than that related to HBV-associated HCC (Table 2).

Previous studies reported that lncRNAs are involved in the pathogenesis of HBV-associated HCC, with functional studies revealing that these lncRNAs contribute also to the onset and progression of HCV-related HCC. Zhang et al. reported LINC01419 transcripts expressed at higher levels in early stage HCC as compared with levels observed in dysplastic tissue. Moreover, this study also reported increased and decreased levels of AK021443 and AF070632 in advanced HCC, respectively, and that LINC01419 and AK021443 regulated the expression of genes associated with cell cycle progression, whereas AF070632 was associated with cofactor binding, oxidation–reduction activity and carboxylic acid catabolic processes.

Upregulated lncRNAs associated with urothelial carcinoma associated-1 (lncRNA-UCA1) and WD-repeat-containing antisense to TP53 (lncRNA-Wrap53) potentially serve as novel serum biomarkers for HCC diagnosis and prognosis. Additionally, the lncRNA associated with activated by TGFβ (lncRNA-ATB) is a key regulator of TGFβ signaling and is positively correlated with the development of liver cirrhosis and HCC-specific vascular invasion. Moreover, lncRNA-ATB might represent a novel diagnostic biomarker and potential therapeutic target for HCV-related hepatic fibrosis. A previous study showed that HCV infection upregulates the expression of miR-373 and Wee1-like protein kinase (WEE1), a pivotal player in the G2/M transition in the cell cycle (although WEE1 is a direct target of miR-373). This study also showed that miR-373 forms a complex with the LINC00657, resulting in release of their common target, WEE1, in HCV-infected cells, and the promotion of uncontrolled cell growth. Another study reported that hypermethylation of promoter regions suppressed mRNA expression, which played a role in the progression of HCV-associated HCC.

6.3. Roles of HCV-coding Proteins

We previously reported the roles for HCV-coding proteins in hepatocarcinogenesis, with the HCV core proteins and NS5A reportedly playing important roles in HCC development. HCV-infected patients showed a higher prevalence of diabetes mellitus and insulin resistance (IR) relative to those with HBV infection. IR measured using a homeostasis model assessment of IR (HOMA-IR) is significantly associated with HCC development in patients with or without chronic HCV infection. Moreover, patients with NASH, which is associated with elevated HOMA-IR, have an increased risk of liver fibrosis, cirrhosis, and HCC.

A previous study showed that the HCV core protein downregulates insulin receptor substrate (IRS)1 and IRS2 by upregulating SOCS3 levels. Moreover, cross-talk between the HCV core protein and molecules regulating insulin signaling might affect HCV-associated hepatocarcinogenesis. Insulin-like growth factors initiate tyrosyl phosphorylation of IRS1 and activate multiple signaling pathways essential for liver growth and HCC, with the activation of IRS1-mediated signaling potentially contributing to hepatic oncogenesis.

CCAAT/enhancer-binding protein (C/EBPβ) and HCV NS5A might be essential components promoting increased gluconeogenesis associated with HCV infection. Previous studies reported the involvement of HCV NS5A in enhanced gluconeogenic gene expression associated with impaired insulin signaling.

Sphere-forming hepatocytes express several cancer stem-like cell (CSC) markers, including c-Kit. Previous studies showed that the HCV core protein significantly upregulates c-Kit expression at the transcriptional level, and that HCV infection potentiates CSC generation. Additionally, a Western diet high in cholesterol and saturated fat (HCFD) in combination with the translation of HCV NS5A stimulates TLR4–Nanog homeobox (NANOG) and leptin receptor–phosphorylated STAT3 signaling, resulting in liver tumorigenesis through an exaggerated mesenchymal phenotype involving prominent Twist1-expressing tumor-initiating stem-like cells expressing NANOG.

7. HCC-specific Molecular Mechanisms from a Therapeutic Point of View

Sorafenib, regorafenib and lenvatinib are approved therapies as oral molecular-targeting drugs for advanced stages of HCC. Sorafenib is an oral serine/threonine kinase inhibitor targeting the extracellular-signaling-regulated kinase/MAPK pathway, vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and epithelial growth factor receptor (EGFR). Additionally, it acts as a tyrosine kinase inhibitor targeting VEGFR1, VEGFR2, VEGFR3, PDGFRβ, ret proto-oncogene (RET), and fms-related tyrosine kinase 3, resulting in the inhibition of tumor proliferation.

Regorafenib is an oral multiple kinase inhibitor of VEGFR1, VEGFR2, VEGFR3, TEK receptor tyrosine kinase, PDGFRβ, fibroblast growth factor receptor (FGFR), proto-oncogene receptor tyrosine kinase (KIT), RET, RAF-1, and B-RAF. Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1/2/3, FGFR1/2/3/4, PDGFRα, KIT, and RET to inhibit tumor angiogenesis and growth. Therefore, sorafenib, regorafenib, and lenvatinib represent multiple kinase inhibitors that do not suppress a specific molecule, thereby restricting their use only in patients with advanced HCC and well-compensated liver function.

Nivolumab, pembrolizumab and tislelizumab are anti-programmed death-1 (PD-1) antibodies. The immune-checkpoint molecule PD-1 is a receptor that negatively regulates immune responses via binding of its representative ligands PD-ligand (PD-L)1 and PD-L2. Inhibition of this pathway can eliminate tumors by recovering their immunosuppressive effects and restoring innate immune activity. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is another counterreceptor for the B7 family of costimulatory molecules and a negative regulator of T cell activation. A blockade of the inhibitory effects of CTLA-4 is supposed to enhance immune responses against tumor cells and also represents a type of immune checkpoint. The blockade of such immune checkpoints represents a promising therapeutic option for HCC; therefore, further studies are needed to determine other immune checkpoints, as well as potential targets of kinase inhibitors related to liver cirrhosis to HCC.

8. Conclusions

This review describes the molecular mechanisms of liver cirrhosis and its progression to HCC (Figure 3). Recent progress in next-generation sequencing has revealed several HCC-specific driver-gene candidates. Additionally, ~70% of HCC cases are caused by HBV and/or HCV infection. Although nucleos(t)ide analogs and direct-acting antivirals can control HBV and HCV replication, HCC occurrence is occasionally observed, and better biomarkers for early detection of HCC are needed. Furthermore, genetic and epigenetic factors, such as miRs, are involved in liver cirrhosis and its progression to HCC. Despite significant advances, additional studies are required to elucidate other molecular mechanisms, including immune checkpoints and molecular targets of kinase inhibitors associated with liver cirrhosis and its progression to HCC.

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    Schachter J., Ribas A., Long G.V., Arance A., Grob J.J., Mortier L., Daud A., Carlino M.S., McNeil C., Lotem M., et al. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390:1853-1862.

    Not in our library10.1016/s0140-6736(17)31601-x

  8. 8.

    Bruix J., Reig M., Sherman M. Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma. Gastroenterology. 2016;150:835-853.

    Not in our library10.1053/j.gastro.2015.12.041

  9. 9.

    Obi S., Yoshida H., Toune R., Unuma T., Kanda M., Sato S., Tateishi R., Teratani T., Shiina S., Omata M. Combination therapy of intraarterial 5-fluorouracil and systemic interferon-alpha for advanced hepatocellular carcinoma with portal venous invasion. Cancer. 2006;106:1990-1997.

    Not in our library10.1002/cncr.21832

  10. 10.

    Kanda T., Takahashi K., Nakamura M., Nakamoto S., Wu S., Haga Y., Sasaki R., Jiang X., Yokosuka O. Androgen Receptor Could Be a Potential Therapeutic Target in Patients with Advanced Hepatocellular Carcinoma. Cancers. 2017;9:43.

    Not in our library10.3390/cancers9050043

  11. 11.

    Fattovich G., Stroffolini T., Zagni I., Donato F. Hepatocellular carcinoma in cirrhosis: Incidence and risk factors. Gastroenterology. 2004;127(Suppl. 1):S35-S50.

    Not in our library10.1053/j.gastro.2004.09.014

  12. 12.

    Bataller R., Brenner D.A. Liver fibrosis. J. Clin. Investig. 2005;115:209-218.

    Not in our library10.1172/jci24282

  13. 13.

    Patel K., Bedossa P., Castera L. Diagnosis of liver fibrosis: Present and future. Semin. Liver Dis. 2015;35:166-183.

    Not in our library10.1055/s-0035-1550059

  14. 14.

    Xu L., Hui A.Y., Albanis E., Arthur M.J., O’Byrne S.M., Blaner W.S., Mukherjee P., Friedman S.L., Eng F.J. Human hepatic stellate cell lines, LX-1 and LX-2: New tools for analysis of hepatic fibrosis. Gut. 2005;54:142-151.

    Not in our library10.1136/gut.2004.042127

  15. 15.

    Okuda K., Nakashima T., Kojiro M., Kondo Y., Wada K. Hepatocellular carcinoma without cirrhosis in Japanese patients. Gastroenterology. 1989;97:140-146.

    Not in our library10.1016/0016-5085(89)91427-3

  16. 16.

    Clouston A.D., Powell E.E., Walsh M.J., Richardson M.M., Demetris A.J., Jonsson J.R. Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis. Hepatology. 2005;41:809-818.

    Not in our library10.1002/hep.20650

  17. 17.

    Lozano R., Naghavi M., Foreman K., Lim S., Shibuya K., Aboyans V., Abraham J., Adair T., Aggarwal R., Ahn S.Y., et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095-2128.

    Not in our library10.1016/s0140-6736(12)61728-0

  18. 18.

    Liaw Y.F., Tai D.I., Chu C.M., Chen T.J. The development of cirrhosis in patients with chronic type B hepatitis: A prospective study. Hepatology. 1988;8:493-496.

    Not in our library10.1002/hep.1840080310

  19. 19.

    Fattovich G., Brollo L., Giustina G., Noventa F., Pontisso P., Alberti A., Realdi G., Ruol A. Natural history and prognostic factors for chronic hepatitis type B. Gut. 1991;32:294-298.

    Not in our library10.1136/gut.32.3.294

  20. 20.

    Sumi H., Yokosuka O., Seki N., Arai M., Imazeki F., Kurihara T., Kanda T., Fukai K., Kato M., Saisho H. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology. 2003;37:19-26.

    Not in our library10.1053/jhep.2003.50036

  21. 21.

    Liaw Y.F., Chen Y.C., Sheen I.S., Chien R.N., Yeh C.T., Chu C.M. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology. 2004;126:1024-1029.

    Not in our library10.1053/j.gastro.2004.01.011

  22. 22.

    Lacombe K., Massari V., Girard P.M., Serfaty L., Gozlan J., Pialoux G., Mialhes P., Molina J.M., Lascoux-Combe C., Wendum D., et al. Major role of hepatitis B genotypes in liver fibrosis during coinfection with HIV. AIDS. 2006;20:419-427.

    Not in our library10.1097/01.aids.0000200537.86984.0e

  23. 23.

    Stroffolini T., Esvan R., Biliotti E., Sagnelli E., Gaeta G.B., Almasio P.L. Gender differences in chronic HBsAg carriers in Italy: Evidence for the independent role of male sex in severity of liver disease. J. Med. Virol. 2015;87:1899-1903.

    Not in our library10.1002/jmv.24243

  24. 24.

    Al-Qahtani A., Khalak H.G., Alkuraya F.S., Al-hamoudi W., Alswat K., Al Balwi M.A., Al Abdulkareem I., Sanai F.M., Abdo A.A. Genome-wide association study of chronic hepatitis B virus infection reveals a novel candidate risk allele on 11q22.3. J. Med. Genet. 2013;50:725-732.

    Not in our library10.1136/jmedgenet-2013-101724

  25. 25.

    Chang S.W., Fann C.S., Su W.H., Wang Y.C., Weng C.C., Yu C.J., Hsu C.L., Hsieh A.R., Chien R.N., Chu C.M., et al. A genome-wide association study on chronic HBV infection and its clinical progression in male Han-Taiwanese. PLoS ONE. 2014;9:e99724.

    Not in our library10.1371/journal.pone.0099724

  26. 26.

    Chu C.M., Liaw Y.F. Hepatitis B virus-related cirrhosis: Natural history and treatment. Semin. Liver Dis. 2006;26:142-152.

    Not in our library10.1055/s-2006-939752

  27. 27.

    Tawada A., Kanda T., Imazeki F., Yokosuka O. Prevention of hepatitis B virus-associated liver diseases by antiviral therapy. Hepatol. Int. 2016;10:574-593.

    Not in our library10.1007/s12072-016-9720-y

  28. 28.

    World Health Organization. Global Hepatitis Report. 2017.

    Not in our library

  29. 29.

    Yang Y.H., Chen W.C., Tsan Y.T., Chen M.J., Shih W.T., Tsai Y.H., Chen P.C. Statin use and the risk of cirrhosis development in patients with hepatitis C virus infection. J. Hepatol. 2015;63:1111-1117.

    Not in our library10.1016/j.jhep.2015.07.006

  30. 30.

    Forns X., Ampurdanès S., Sanchez-Tapias J.M., Guilera M., Sans M., Sánchez-Fueyo A., Quintó L., Joya P., Bruguera M., Rodés J. Long-term follow-up of chronic hepatitis C in patients diagnosed at a tertiary-care center. J. Hepatol. 2001;35:265-271.

    Not in our library10.1016/s0168-8278(01)00088-5

  31. 31.

    Westin J., Nordlinder H., Lagging M., Norkrans G., Wejstål R. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J. Hepatol. 2002;37:837-842.

    Not in our library10.1016/s0168-8278(02)00299-4

  32. 32.

    Rubbia-Brandt L., Fabris P., Paganin S., Leandro G., Male P.J., Giostra E., Carlotto A., Bozzola L., Smedile A., Negro F. Steatosis affects chronic hepatitis C progression in a genotype specific way. Gut. 2004;53:406-412.

    Not in our library10.1136/gut.2003.018770

  33. 33.

    Locasciulli A., Testa M., Pontisso P., Benvegnù L., Fraschini D., Corbetta A., Noventa F., Masera G., Alberti A. Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood. 1997;90:4628-4633.

    Not in our library

  34. 34.

    Kenny-Walsh E. Clinical outcomes after hpatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N. Engl. J. Med. 1999;340:1228-1233.

    Not in our library10.1056/nejm199904223401602

  35. 35.

    Poynard T., Bedossa P., Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825-832.

    Not in our library10.1016/s0140-6736(96)07642-8

  36. 36.

    Poynard T., Ratziu V., Charlotte F., Goodman Z., McHutchison J., Albrecht J. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c. J. Hepatol. 2001;34:730-739.

    Not in our library10.1016/s0168-8278(00)00097-0

  37. 37.

    Shiffman M.L. Natural history and risk factors for progression of hepatitis C virus disease and development of hepatocellular cancer before liver transplantation. Liver Transpl. 2003;9:S14-S20.

    Not in our library10.1053/jlts.2003.50254

  38. 38.

    Fuster D., Planas R., Muga R., Ballesteros A.L., Santos J., Tor J., Sirera G., Guardiola H., Salas A., Cabré E., et al. Advanced liver fibrosis in HIV/HCV-coinfected patients on antiretroviral therapy. AIDS Res. Hum. Retrovir. 2004;20:1293-1297.

    Not in our library10.1089/aid.2004.20.1293

  39. 39.

    Ribes J., Clèries R., Rubió A., Hernández J.M., Mazzara R., Madoz P., Casanovas T., Casanova A., Gallen M., Rodríguez C., et al. Cofactors associated with liver disease mortality in an HBsAg-positive Mediterranean cohort: 20 years of follow-up. Int. J. Cancer. 2006;119:687-694.

    Not in our library10.1002/ijc.21882

  40. 40.

    Wilson L.E., Torbenson M., Astemborski J., Faruki H., Spoler C., Rai R., Mehta S., Kirk G.D., Nelson K., Afdhal N., et al. Progression of liver fibrosis among injection drug users with chronic hepatitis C. Hepatology. 2006;43:788-795.

    Not in our library10.1002/hep.21091

  41. 41.

    Petta S., Cammà C., Di Marco V., Alessi N., Cabibi D., Caldarella R., Licata A., Massenti F., Tarantino G., Marchesini G., et al. Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection. Am. J. Gastroenterol. 2008;103:1136-1144.

    Not in our library10.1111/j.1572-0241.2008.01813.x

  42. 42.

    Dyal H.K., Aguilar M., Bhuket T., Liu B., Holt E.W., Torres S., Cheung R., Wong R.J. Concurrent Obesity, Diabetes, and Steatosis Increase Risk of Advanced Fibrosis Among HCV Patients: A Systematic Review. Dig. Dis. Sci. 2015;60:2813-2824.

    Not in our library10.1007/s10620-015-3760-3

  43. 43.

    Shiratori Y., Imazeki F., Moriyama M., Yano M., Arakawa Y., Yokosuka O., Kuroki T., Nishiguchi S., Sata M., Yamada G., et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann. Intern. Med. 2000;132:517-524.

    Not in our library10.7326/0003-4819-132-7-200004040-00002

  44. 44.

    Caporaso N., Romano M., Marmo R., de Sio I., Morisco F., Minerva A., Coltorti M. Hepatitis C virus infection is an additive risk factor for development of hepatocellular carcinoma in patients with cirrhosis. J. Hepatol. 1991;12:367-371.

    Not in our library10.1016/0168-8278(91)90841-x

  45. 45.

    Benvegnù L., Fattovich G., Noventa F., Tremolada F., Chemello L., Cecchetto A., Alberti A. Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer. 1994;74:2442-2448.

    Not in our library10.1002/1097-0142(19941101)74:9<2442::aid-cncr2820740909>3.0.co;2-#

  46. 46.

    Ishikawa T., Ichida T., Yamagiwa S., Sugahara S., Uehara K., Okoshi S., Asakura H. High viral loads, serum alanine aminotransferase and gender are predictive factors for the development of hepatocellular carcinoma from viral compensated liver cirrhosis. J. Gastroenterol. Hepatol. 2001;16:1274-1281.

    Not in our library10.1046/j.1440-1746.2001.02616.x

  47. 47.

    Ohata K., Hamasaki K., Toriyama K., Matsumoto K., Saeki A., Yanagi K., Abiru S., Nakagawa Y., Shigeno M., Miyazoe S., et al. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer. 2003;97:3036-3043.

    Not in our library10.1002/cncr.11427

  48. 48.

    Yoshida H., Shiratori Y., Moriyama M., Arakawa Y., Ide T., Sata M., Inoue O., Yano M., Tanaka M., Fujiyama S., et al. Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann. Intern. Med. 1999;131:174-181.

    Not in our library10.7326/0003-4819-131-3-199908030-00003

  49. 49.

    Alberti A., Piovesan S. Increased incidence of liver cancer after successful DAA treatment of chronic hepatitis C: Fact or fiction? Liver Int. 2017;37:802-808.

    Not in our library10.1111/liv.13390

  50. 50.

    El Kassas M., Funk A.L., Salaheldin M., Shimakawa Y., Eltabbakh M., Jean K., El Tahan A., Sweedy A.T., Afify S., Youssef N.F., et al. Increased recurrence rates of hepatocellular carcinoma after DAA therapy in a hepatitis C-infected Egyptian cohort: A comparative analysis. J. Viral Hepat. 2018;25:623-630.

    Not in our library10.1111/jvh.12854

  51. 51.

    Sasaki R., Kanda T., Kato N., Yokosuka O., Moriyama M. Hepatitis C virus-associated hepatocellular carcinoma after sustained virologic response. World J. Hepatol. 2018;10:898-906.

    Not in our library10.4254/wjh.v10.i12.898

  52. 52.

    Totoki Y., Tatsuno K., Covington K.R., Ueda H., Creighton C.J., Kato M., Tsuji S., Donehower L.A., Slagle B.L., Nakamura H., et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet. 2014;46:1267-1273.

    Not in our library10.1038/ng.3126

  53. 53.

    Fujimoto A., Totoki Y., Abe T., Boroevich K.A., Hosoda F., Nguyen H.H., Aoki M., Hosono N., Kubo M., Miya F., et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat. Genet. 2012;44:760-764.

    Not in our library10.1038/ng.2291

  54. 54.

    Huang J., Deng Q., Wang Q., Li K.Y., Dai J.H., Li N., Zhu Z.D., Zhou B., Liu X.Y., Liu R.F., et al. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat. Genet. 2012;44:1117-1121.

    Not in our library10.1038/ng.2391

  55. 55.

    Schulze K., Imbeaud S., Letouzé E., Alexandrov L.B., Calderaro J., Rebouissou S., Couchy G., Meiller C., Shinde J., Soysouvanh F., et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 2015;47:505-511.

    Not in our library10.1038/ng.3252

  56. 56.

    Nault J.C., Mallet M., Pilati C., Calderaro J., Bioulac-Sage P., Laurent C., Laurent A., Cherqui D., Balabaud C., Zucman-Rossi J. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun. 2013;4:2218.

    Not in our library10.1038/ncomms3218

  57. 57.

    Li M., Zhao H., Zhang X., Wood L.D., Anders R.A., Choti M.A., Pawlik T.M., Daniel H.D., Kannangai R., Offerhaus G.J., et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat. Genet. 2011;43:828-829.

    Not in our library10.1038/ng.903

  58. 58.

    Moore A., Wu L., Chuang J.C., Sun X., Luo X., Gopal P., Li L., Celen C., Zimmer M., Zhu H. Arid1a loss drives non-alcoholic steatohepatitis in mice via epigenetic dysregulation of hepatic lipogenesis and fatty acid oxidation. Hepatology. 2018.

    Not in our library10.1002/hep.30487

  59. 59.

    Nose H., Imazeki F., Ohto M., Omata M. p53 gene mutations and 17p allelic deletions in hepatocellular carcinoma from Japan. Cancer. 1993;72:355-3560.

    Not in our library10.1002/1097-0142(19930715)72:2<355::aid-cncr2820720208>3.0.co;2-w

  60. 60.

    Imazeki F., Yokosuka O., Ohto M., Omata M. Aflatoxin and p53 abnormality in duck hepatocellular carcinoma. J. Gastroenterol. Hepatol. 1995;10:646-649.

    Not in our library10.1111/j.1440-1746.1995.tb01364.x

  61. 61.

    Ray R.B., Meyer K., Ray R. Suppression of apoptotic cell death by hepatitis C virus core protein. Virology. 1996;226:176-182.

    Not in our library10.1006/viro.1996.0644

  62. 62.

    Ray R.B., Steele R., Meyer K., Ray R. Hepatitis C virus core protein represses p21WAF1/Cip1/Sid1 promoter activity. Gene. 1998;208:331-336.

    Not in our library10.1016/s0378-1119(98)00030-4

  63. 63.
    Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53 · 2015
    No notice
  64. 64.

    Wong C.M., Wei L., Law C.T., Ho D.W., Tsang F.H., Au S.L., Sze K.M., Lee J.M., Wong C.C., Ng I.O. Up-regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis. Hepatology. 2016;63:474-487.

    Not in our library10.1002/hep.28304

  65. 65.

    Kodama T., Newberg J.Y., Kodama M., Rangel R., Yoshihara K., Tien J.C., Parsons P.H., Wu H., Finegold M.J., Copeland N.G., et al. Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA. 2016;113:E3384-E3393.

    Not in our library10.1073/pnas.1606876113

  66. 66.

    Harding J.J., Nandakumar S., Armenia J., Khalil D.N., Albano M., Ly M., Shia J., Hechtman J.F., Kundra R., El Dika I., et al. Prospective Genotyping of Hepatocellular Carcinoma: Clinical Implications of Next Generation Sequencing for Matching Patients to Targeted and Immune Therapies. Clin. Cancer Res. 2018.

    Not in our library10.1158/1078-0432.ccr-18-2293

  67. 67.

    Inami Y., Waguri S., Sakamoto A., Kouno T., Nakada K., Hino O., Watanabe S., Ando J., Iwadate M., Yamamoto M., et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J. Cell Biol. 2011;193:275-284.

    Not in our library10.1083/jcb.201102031

  68. 68.

    Zavattari P., Perra A., Menegon S., Kowalik M.A., Petrelli A., Angioni M.M., Follenzi A., Quagliata L., Ledda-Columbano G.M., Terracciano L., et al. Nrf2, but not β-catenin, mutation represents an early event in rat hepatocarcinogenesis. Hepatology. 2015;62:851-862.

    Not in our library10.1002/hep.27790

  69. 69.

    Bartolini D., Dallaglio K., Torquato P., Piroddi M., Galli F. Nrf2-p62 autophagy pathway and its response to oxidative stress in hepatocellular carcinoma. Transl. Res. 2018;193:54-71.

    Not in our library10.1016/j.trsl.2017.11.007

  70. 70.

    Fujimoto A., Furuta M., Totoki Y., Tsunoda T., Kato M., Shiraishi Y., Tanaka H., Taniguchi H., Kawakami Y., Ueno M., et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat. Genet. 2016;48:500-509.

    Not in our library10.1038/ng.3547

  71. 71.

    Kojima H., Yokosuka O., Imazeki F., Saisho H., Omata M. Telomerase activity and telomere length in hepatocellular carcinoma and chronic liver disease. Gastroenterology. 1997;112:493-500.

    Not in our library10.1053/gast.1997.v112.pm9024303

  72. 72.

    Tokino T., Matsubara K. Chromosomal sites for hepatitis B virus integration in human hepatocellular carcinoma. J. Virol. 1991;65:6761-6764.

    Not in our library10.1128/jvi.65.12.6761-6764.1991

  73. 73.

    Nagaya T., Nakamura T., Tokino T., Tsurimoto T., Imai M., Mayumi T., Kamino K., Yamamura K., Matsubara K. The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma. Genes Dev. 1987;1:773-782.

    Not in our library10.1101/gad.1.8.773

  74. 74.

    Imazeki F., Omata M., Yokosuka O., Okuda K. Integration of hepatitis B virus DNA in hepatocellular carcinoma. Cancer. 1986;58:1055-1060.

    Not in our library10.1002/1097-0142(19860901)58:5<1055::aid-cncr2820580513>3.0.co;2-#

  75. 75.

    Wang M., Xi D., Ning Q. Virus-induced hepatocellular carcinoma with special emphasis on HBV. Hepatol. Int. 2017;11:171-180.

    Not in our library10.1007/s12072-016-9779-5

  76. 76.

    Meyerson M., Counter C.M., Eaton E.N., Ellisen L.W., Steiner P., Caddle S.D., Ziaugra L., Beijersbergen R.L., Davidoff M.J., Liu Q., et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell. 1997;90:785-795.

    Not in our library10.1016/s0092-8674(00)80538-3

  77. 77.

    Tokino T., Fukushige S., Nakamura T., Nagaya T., Murotsu T., Shiga K., Aoki N., Matsubara K. Chromosomal translocation and inverted duplication associated with integrated hepatitis B virus in hepatocellular carcinomas. J. Virol. 1987;61:3848-3854.

    Not in our library10.1128/jvi.61.12.3848-3854.1987

  78. 78.

    Koike K., Shirakata Y., Yaginuma K., Arii M., Takada S., Nakamura I., Hayashi Y., Kawada M., Kobayashi M. Oncogenic potential of hepatitis B virus. Mol. Biol. Med. 1989;6:151-160.

    Not in our library

  79. 79.

    Kanda T., Yokosuka O., Imazeki F., Yamada Y., Imamura T., Fukai K., Nagao K., Saisho H. Hepatitis B virus X protein (HBx)-induced apoptosis in HuH-7 cells: Influence of HBV genotype and basal core promoter mutations. Scand. J. Gastroenterol. 2004;39:478-485.

    Not in our library10.1080/00365520310008719

  80. 80.

    Liu H., Shi W., Luan F., Xu S., Yang F., Sun W., Liu J., Ma C. Hepatitis B virus X protein upregulates transcriptional activation of human telomerase reverse transcriptase. Virus Genes. 2010;40:174-182.

    Not in our library10.1007/s11262-009-0441-3

  81. 81.

    Zou S.Q., Qu Z.L., Li Z.F., Wang X. Hepatitis B virus X gene induces human telomerase reverse transcriptase mRNA expression in cultured normal human cholangiocytes. World J. Gastroenterol. 2004;10:2259-2262.

    Not in our library10.3748/wjg.v10.i15.2259

  82. 82.

    Kojima H., Kaita K.D., Xu Z., Ou J.H., Gong Y., Zhang M., Minuk G.Y. The absence of up-regulation of telomerase activity during regeneration after partial hepatectomy in hepatitis B virus X gene transgenic mice. J. Hepatol. 2003;39:262-268.

    Not in our library10.1016/s0168-8278(03)00215-0

  83. 83.

    Sung W.K., Zheng H., Li S., Chen R., Liu X., Li Y., Lee N.P., Lee W.H., Ariyaratne P.N., Tennakoon C., et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat. Genet. 2012;44:765-769.

    Not in our library10.1038/ng.2295

  84. 84.

    Nakano M., Kawaguchi T., Nakamoto S., Kawaguchi A., Kanda T., Imazeki F., Kuromatsu R., Sumie S., Satani M., Yamada S., et al. Effect of occult hepatitis B virus infection on the early-onset of hepatocellular carcinoma in patients with hepatitis C virus infection. Oncol. Rep. 2013;30:2049-2055.

    Not in our library10.3892/or.2013.2700

  85. 85.

    Mason W.S., Gill U.S., Litwin S., Zhou Y., Peri S., Pop O., Hong M.L., Naik S., Quaglia A., Bertoletti A., et al. HBV DNA Integration and Clonal Hepatocyte Expansion in Chronic Hepatitis B Patients Considered Immune Tolerant. Gastroenterology. 2016;151:986-998.

    Not in our library10.1053/j.gastro.2016.07.012

  86. 86.

    Kennedy P.T.F., Litwin S., Dolman G.E., Bertoletti A., Mason W.S. Immune Tolerant Chronic Hepatitis B: The Unrecognized Risks. Viruses. 2017;9:96.

    Not in our library10.3390/v9050096

  87. 87.

    Wu S., Kanda T., Nakamoto S., Jiang X., Nakamura M., Sasaki R., Haga Y., Shirasawa H., Yokosuka O. Cooperative effects of hepatitis B virus and TNF may play important roles in the activation of metabolic pathways through the activation of NF-κB. Int. J. Mol. Med. 2016;38:475-481.

    Not in our library10.3892/ijmm.2016.2643

  88. 88.

    Xie Y. Hepatitis B Virus-Associated Hepatocellular Carcinoma. Adv. Exp. Med. Biol. 2017;1018:11-21.

    Not in our library10.1007/978-981-10-5765-6_2

  89. 89.

    Jiang X., Kanda T., Wu S., Nakamura M., Miyamura T., Nakamoto S., Banerjee A., Yokosuka O. Regulation of microRNA by hepatitis B virus infection and their possible association with control of innate immunity. World J. Gastroenterol. 2014;20:7197-7206.

    Not in our library10.3748/wjg.v20.i23.7197

  90. 90.

    Sarkar N., Panigrahi R., Pal A., Biswas A., Singh S.P., Kar S.K., Bandopadhyay M., Das D., Saha D., Kanda T., et al. Expression of microRNA-155 correlates positively with the expression of Toll-like receptor 7 and modulates hepatitis B virus via C/EBP-β in hepatocytes. J. Viral Hepat. 2015;22:817-827.

    Not in our library10.1111/jvh.12390

  91. 91.

    Wang W., Bian H., Li F., Li X., Zhang D., Sun S., Song S., Zhu Q., Ren W., Qin C., et al. HBeAg induces the expression of macrophage miR-155 to accelerate liver injury via promoting production of inflammatory cytokines. Cell. Mol. Life Sci. 2018;75:2627-2641.

    Not in our library10.1007/s00018-018-2753-8

  92. 92.

    Wong Q.W., Lung R.W., Law P.T., Lai P.B., Chan K.Y., To K.F., Wong N. MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology. 2008;135:257-269.

    Not in our library10.1053/j.gastro.2008.04.003

  93. 93.

    Zhang X., Liu S., Hu T., Liu S., He Y., Sun S. Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology. 2009;50:490-499.

    Not in our library10.1002/hep.23008

  94. 94.

    Yang L., Ma Z., Wang D., Zhao W., Chen L., Wang G. MicroRNA-602 regulating tumor suppressive gene RASSF1A is overexpressed in hepatitis B virus-infected liver and hepatocellular carcinoma. Cancer Biol. Ther. 2010;9:803-808.

    Not in our library10.4161/cbt.9.10.11440

  95. 95.

    Wang Y., Lu Y., Toh S.T., Sung W.K., Tan P., Chow P., Chung A.Y., Jooi L.L., Lee C.G. Lethal-7 is down-regulated by the hepatitis B virus x protein and targets signal transducer and activator of transcription 3. J. Hepatol. 2010;53:57-66.

    Not in our library10.1016/j.jhep.2009.12.043

  96. 96.

    Huang J., Wang Y., Guo Y., Sun S. Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology. 2010;52:60-70.

    Not in our library10.1002/hep.23660

  97. 97.

    Li L.M., Hu Z.B., Zhou Z.X., Chen X., Liu F.Y., Zhang J.F., Shen H.B., Zhang C.Y., Zen K. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res. 2010;70:9798-9807.

    Not in our library10.1158/0008-5472.can-10-1001

  98. 98.

    Gao P., Wong C.C., Tung E.K., Lee J.M., Wong C.M., Ng I.O. Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesis. J. Hepatol. 2011;54:1177-1184.

    Not in our library10.1016/j.jhep.2010.09.023

  99. 99.

    Jiang R., Deng L., Zhao L., Li X., Zhang F., Xia Y., Gao Y., Wang X., Sun B. miR-22 promotes HBV-related hepatocellular carcinoma development in males. Clin. Cancer Res. 2011;17:5593-5603.

    Not in our library10.1158/1078-0432.ccr-10-1734

  100. 100.

    Wang C.M., Wang Y., Fan C.G., Xu F.F., Sun W.S., Liu Y.G., Jia J.H. miR-29c targets TNFAIP3, inhibits cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma. Biochem. Biophys. Res. Commun. 2011;411:586-592.

    Not in our library10.1016/j.bbrc.2011.06.191

  101. 101.
    Serum MicroRNAs as Biomarkers for Hepatocellular Carcinoma in Chinese Patients with Chronic Hepatitis B Virus Infection · 2011
    No notice
  102. 102.

    Cardin R., Piciocchi M., Sinigaglia A., Lavezzo E., Bortolami M., Kotsafti A., Cillo U., Zanus G., Mescoli C., Rugge M., et al. Oxidative DNA damage correlates with cell immortalization and mir-92 expression in hepatocellular carcinoma. BMC Cancer. 2012;12:177.

    Not in our library10.1186/1471-2407-14-284

  103. 103.

    Li L., Guo Z., Wang J., Mao Y., Gao Q. Serum miR-18a: A potential marker for hepatitis B virus-related hepatocellular carcinoma screening. Dig. Dis. Sci. 2012;57:2910-2916.

    Not in our library10.1007/s10620-012-2317-y

  104. 104.

    Fu X., Tan D., Hou Z., Hu Z., Liu G. miR-338-3p is down-regulated by hepatitis B virus X and inhibits cell proliferation by targeting the 3’-UTR region of CyclinD1. Int. J. Mol. Sci. 2012;13:8514-8539.

    Not in our library10.3390/ijms13078514

  105. 105.

    Yang P., Li Q.J., Feng Y., Zhang Y., Markowitz G.J., Ning S., Deng Y., Zhao J., Jiang S., Yuan Y., et al. TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell. 2012;22:291-303.

    Not in our library10.1016/j.ccr.2012.07.023

  106. 106.

    Wei X., Xiang T., Ren G., Tan C., Liu R., Xu X., Wu Z. miR-101 is down-regulated by the hepatitis B virus x protein and induces aberrant DNA methylation by targeting DNA methyltransferase 3A. Cell. Signal. 2013;25:439-446.

    Not in our library10.1016/j.cellsig.2012.10.013

  107. 107.

    Li C., Wang Y., Wang S., Wu B., Hao J., Fan H., Ju Y., Ding Y., Chen L., Chu X., et al. Hepatitis B virus mRNA-mediated miR-122 inhibition upregulates PTTG1-binding protein, which promotes hepatocellular carcinoma tumor growth and cell invasion. J. Virol. 2013;87:2193-2205.

    Not in our library10.1128/jvi.02831-12

  108. 108.

    Xu X., Fan Z., Kang L., Han J., Jiang C., Zheng X., Zhu Z., Jiao H., Lin J., Jiang K., et al. Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J. Clin. Investig. 2013;123:630-645.

    Not in our library10.1172/jci64265

  109. 109.

    Shi C., Xu X. MicroRNA-22 is down-regulated in hepatitis B virus-related hepatocellular carcinoma. Biomed. Pharmacother. 2013;67:375-380.

    Not in our library10.1016/j.biopha.2013.03.002

  110. 110.

    Lan S.H., Wu S.Y., Zuchini R., Lin X.Z., Su I.J., Tsai T.F., Lin Y.J., Wu C.T., Liu H.S. Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224. Hepatology. 2014;59:505-517.

    Not in our library10.1002/hep.26659

  111. 111.

    Fu Y., Wei X., Tang C., Li J., Liu R., Shen A., Wu Z. Circulating microRNA-101 as a potential biomarker for hepatitis B virus-related hepatocellular carcinoma. Oncol. Lett. 2013;6:1811-1815.

    Not in our library10.3892/ol.2013.1638

  112. 112.

    Li J., Shi W., Gao Y., Yang B., Jing X., Shan S., Wang Y., Du Z. Analysis of microRNA expression profiles in human hepatitis B virus-related hepatocellular carcinoma. Clin. Lab. 2013;59:1009-1015.

    Not in our library10.7754/clin.lab.2012.120901

  113. 113.

    Zhang T., Zhang J., Cui M., Liu F., You X., Du Y., Gao Y., Zhang S., Lu Z., Ye L., et al. Hepatitis B virus X protein inhibits tumor suppressor miR-205 through inducing hypermethylation of miR-205 promoter to enhance carcinogenesis. Neoplasia. 2013;15:1282-1291.

    Not in our library10.1593/neo.131362

  114. 114.

    Sheng Y., Li J., Zou C., Wang S., Cao Y., Zhang J., Huang A., Tang H. Downregulation of miR-101-3p by hepatitis B virus promotes proliferation and migration of hepatocellular carcinoma cells by targeting Rab5a. Arch. Virol. 2014;159:2397-2410.

    Not in our library10.1007/s00705-014-2084-5

  115. 115.

    Dang Y.W., Zeng J., He R.Q., Rong M.H., Luo D.Z., Chen G. Effects of miR-152 on cell growth inhibition, motility suppression and apoptosis induction in hepatocellular carcinoma cells. Asian Pac. J. Cancer Prev. 2014;15:4969-4976.

    Not in our library10.7314/apjcp.2014.15.12.4969

  116. 116.

    Lan S.H., Wu S.Y., Zuchini R., Lin X.Z., Su I.J., Tsai T.F., Lin Y.J., Wu C.T., Liu H.S. Autophagy-preferential degradation of MIR224 participates in hepatocellular carcinoma tumorigenesis. Autophagy. 2014;10:1687-1689.

    Not in our library10.4161/auto.29959

  117. 117.

    Meng F.L., Wang W., Jia W.D. Diagnostic and prognostic significance of serum miR-24-3p in HBV-related hepatocellular carcinoma. Med. Oncol. 2014;31:177.

    Not in our library10.1007/s12032-014-0177-3

  118. 118.

    Bandopadhyay M., Banerjee A., Sarkar N., Panigrahi R., Datta S., Pal A., Singh S.P., Biswas A., Chakrabarti S., Chakravarty R. Tumor suppressor micro RNA miR-145 and onco micro RNAs miR-21 and miR-222 expressions are differentially modulated by hepatitis B virus X protein in malignant hepatocytes. BMC Cancer. 2014;14:721.

    Not in our library10.1186/1471-2407-14-721

  119. 119.

    Xing T.J., Jiang D.F., Huang J.X., Xu Z.L. Expression and clinical significance of miR-122 and miR-29 in hepatitis B virus-related liver disease. Genet. Mol. Res. 2014;13:7912-7918.

    Not in our library10.4238/2014.september.29.4

  120. 120.

    Zhao Q., Li T., Qi J., Liu J., Qin C. The miR-545/374a cluster encoded in the Ftx lncRNA is overexpressed in HBV-related hepatocellular carcinoma and promotes tumorigenesis and tumor progression. PLoS ONE. 2014;9:e109782.

    Not in our library10.1371/journal.pone.0109782

  121. 121.

    Gao H., Liu C. miR-429 represses cell proliferation and induces apoptosis in HBV-related HCC. Biomed. Pharmacother. 2014;68:943-949.

    Not in our library10.1016/j.biopha.2014.09.005

  122. 122.

    Liu F.Y., Zhou S.J., Deng Y.L., Zhang Z.Y., Zhang E.L., Wu Z.B., Huang Z.Y., Chen X.P. MiR-216b is involved in pathogenesis and progression of hepatocellular carcinoma through HBx-miR-216b-IGF2BP2 signaling pathway. Cell Death Dis. 2015;6:e1670.

    Not in our library10.1038/cddis.2015.46

  123. 123.

    Yu F., Lu Z., Chen B., Dong P., Zheng J. microRNA-150: A promising novel biomarker for hepatitis B virus-related hepatocellular carcinoma. Diagn. Pathol. 2015;10:129.

    Not in our library10.1186/s13000-015-0369-y

  124. 124.

    Cao Y., Chen J., Wang D., Peng H., Tan X., Xiong D., Huang A., Tang H. Upregulated in Hepatitis B virus-associated hepatocellular carcinoma cells, miR-331-3p promotes proliferation of hepatocellular carcinoma cells by targeting ING5. Oncotarget. 2015;6:38093-38106.

    Not in our library10.18632/oncotarget.5642

  125. 125.

    Gao F., Sun X., Wang L., Tang S., Yan C. Downregulation of MicroRNA-145 Caused by Hepatitis B Virus X Protein Promotes Expression of CUL5 and Contributes to Pathogenesis of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cell. Physiol. Biochem. 2015;37:1547-1559.

    Not in our library10.1159/000438522

  126. 126.

    Shao J., Cao J., Liu Y., Mei H., Zhang Y., Xu W. MicroRNA-519a promotes proliferation and inhibits apoptosis of hepatocellular carcinoma cells by targeting FOXF2. FEBS Open Bio. 2015;5:893-899.

    Not in our library10.1016/j.fob.2015.10.009

  127. 127.

    Wang Y., Wang C.M., Jiang Z.Z., Yu X.J., Fan C.G., Xu F.F., Zhang Q., Li L.I., Li R.F., Sun W.S., et al. MicroRNA-34c targets TGFB-induced factor homeobox 2, represses cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma. Oncol. Lett. 2015;10:3095-3102.

    Not in our library10.3892/ol.2015.3649

  128. 128.

    Ghosh A., Ghosh A., Datta S., Dasgupta D., Das S., Ray S., Gupta S., Datta S., Chowdhury A., Chatterjee R., et al. Hepatic miR-126 is a potential plasma biomarker for detection of hepatitis B virus infected hepatocellular carcinoma. Int. J. Cancer. 2016;138:2732-2744.

    Not in our library10.1002/ijc.29999

  129. 129.

    Chen Y., Dong X., Yu D., Wang X. Serum miR-96 is a promising biomarker for hepatocellular carcinoma in patients with chronic hepatitis B virus infection. Int. J. Clin. Exp. Med. 2015;8:18462-18468.

    Not in our library

  130. 130.

    Chen S., Chen H., Gao S., Qiu S., Zhou H., Yu M., Tu J. Differential expression of plasma microRNA-125b in hepatitis B virus-related liver diseases and diagnostic potential for hepatitis B virus-induced hepatocellular carcinoma. Hepatol. Res. 2017;47:312-320.

    Not in our library10.1111/hepr.12739

  131. 131.

    Yen C.S., Su Z.R., Lee Y.P., Liu I.T., Yen C.J. miR-106b promotes cancer progression in hepatitis B virus-associated hepatocellular carcinoma. World J. Gastroenterol. 2016;22:5183-5192.

    Not in our library10.3748/wjg.v22.i22.5183

  132. 132.

    Kong X.X., Lv Y.R., Shao L.P., Nong X.Y., Zhang G.L., Zhang Y., Fan H.X., Liu M., Li X., Tang H. HBx-induced MiR-1269b in NF-κB dependent manner upregulates cell division cycle 40 homolog (CDC40) to promote proliferation and migration in hepatoma cells. J. Transl. Med. 2016;14:189.

    Not in our library10.1186/s12967-016-0949-y

  133. 133.

    Liu X., Zhang Y., Wang P., Wang H., Su H., Zhou X., Zhang L. HBX Protein-Induced Downregulation of microRNA-18a is Responsible for Upregulation of Connective Tissue Growth Factor in HBV Infection-Associated Hepatocarcinoma. Med. Sci. Monit. 2016;22:2492-2500.

    Not in our library10.12659/msm.895943

  134. 134.

    Qiao D.D., Yang J., Lei X.F., Mi G.L., Li S.L., Li K., Xu C.Q., Yang H.L. Expression of microRNA-122 and microRNA-22 in HBV-related liver cancer and the correlation with clinical features. Eur. Rev. Med. Pharmacol. Sci. 2017;21:742-747.

    Not in our library

  135. 135.

    Qin X., Chen J., Wu L., Liu Z. MiR-30b-5p acts as a tumor suppressor, repressing cell proliferation and cell cycle in human hepatocellular carcinoma. Biomed. Pharmacother. 2017;89:742-750.

    Not in our library10.1016/j.biopha.2017.02.062

  136. 136.

    Bai P.S., Xia N., Sun H., Kong Y. Pleiotrophin, a target of miR-384, promotes proliferation, metastasis and lipogenesis in HBV-related hepatocellular carcinoma. J. Cell. Mol. Med. 2017;21:3023-3043.

    Not in our library10.1111/jcmm.13213

  137. 137.

    Li G., Zhang W., Gong L., Huang X. MicroRNA-125a-5p Inhibits Cell Proliferation and Induces Apoptosis in Hepatitis B Virus-Related Hepatocellular Carcinoma by Downregulation of ErbB3. Oncol. Res. 2017.

    Not in our library10.3727/096504017x15016337254623

  138. 138.

    Zhao Q., Sun X., Liu C., Li T., Cui J., Qin C. Expression of the microRNA-143/145 cluster is decreased in hepatitis B virus-associated hepatocellular carcinoma and may serve as a biomarker for tumorigenesis in patients with chronic hepatitis B. Oncol. Lett. 2018;15:6115-6122.

    Not in our library10.3892/ol.2018.8117

  139. 139.

    Quoc N.B., Phuong N.D.N., Ngan T.K., Linh N.T.M., Cuong P.H., Chau N.N.B. Expression of Plasma hsa-miR122 in HBV-Related Hepatocellular Carcinoma (HCC) in Vietnamese Patients. Microrna. 2018;7:92-99.

    Not in our library10.2174/2211536607666180427165114

  140. 140.

    Jones K.R., Nabinger S.C., Lee S., Sahu S.S., Althouse S., Saxena R., Johnson M.S., Chalasani N., Gawrieh S., Kota J. Lower expression of tumor microRNA-26a is associated with higher recurrence in patients with hepatocellular carcinoma undergoing surgical treatment. J. Surg. Oncol. 2018;118:431-439.

    Not in our library10.1002/jso.25156

  141. 141.

    Yang L., Guo Y., Liu X., Wang T., Tong X., Lei K., Wang J., Huang D., Xu Q. The tumor suppressive miR-302c-3p inhibits migration and invasion of hepatocellular carcinoma cells by targeting TRAF4. J. Cancer. 2018;9:2693-2701.

    Not in our library10.7150/jca.25569

  142. 142.

    Chen Y., Zhao Z.X., Huang F., Yuan X.W., Deng L., Tang D. MicroRNA-1271 functions as a potential tumor suppressor in hepatitis B virus-associated hepatocellular carcinoma through the AMPK signaling pathway by binding to CCNA1. J. Cell. Physiol. 2018.

    Not in our library10.1002/jcp.26955

  143. 143.

    Qiu L., Wang T., Xu X., Wu Y., Tang Q., Chen K. Long Non-Coding RNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Regulation, Functions, and Underlying Mechanisms. Int. J. Mol. Sci. 2017;18:2505.

    Not in our library10.3390/ijms18122505

  144. 144.

    Cui S., Qian Z., Chen Y., Li L., Li P., Ding H. Screening of up- and downregulation of circRNAs in HBV-related hepatocellular carcinoma by microarray. Oncol. Lett. 2018;15:423-432.

    Not in our library10.3892/ol.2017.7265

  145. 145.

    Wang S., Cui S., Zhao W., Qian Z., Liu H., Chen Y., Lv F., Ding H.G. Screening and bioinformatics analysis of circular RNA expression profiles in hepatitis B-related hepatocellular carcinoma. Cancer Biomark. 2018;22:631-640.

    Not in our library10.3233/cbm-170910

  146. 146.

    Matsuda Y., Ichida T., Genda T., Yamagiwa S., Aoyagi Y., Asakura H. Loss of p16 contributes to p27 sequestration by cyclin D(1)-cyclin-dependent kinase 4 complexes and poor prognosis in hepatocellular carcinoma. Clin. Cancer Res. 2003;9:3389-3396.

    Not in our library

  147. 147.

    Pezzuto F., Buonaguro L., Buonaguro F.M., Tornesello M.L. The Role of Circulating Free DNA and MicroRNA in Non-Invasive Diagnosis of HBV- and HCV-Related Hepatocellular Carcinoma. Int. J. Mol. Sci. 2018;19:1007.

    Not in our library10.3390/ijms19041007

  148. 148.

    Tian Y., Ou J.H. Genetic and epigenetic alterations in hepatitis B virus-associated hepatocellular carcinoma. Virol. Sin. 2015;30:85-91.

    Not in our library10.1007/s12250-015-3582-7

  149. 149.

    Wu S., Kanda T., Imazeki F., Arai M., Yonemitsu Y., Nakamoto S., Fujiwara K., Fukai K., Nomura F., Yokosuka O. Hepatitis B virus e antigen downregulates cytokine production in human hepatoma cell lines. Viral Immunol. 2010;23:467-476.

    Not in our library10.1089/vim.2010.0042

  150. 150.

    Hadziyannis E., Laras A. Viral Biomarkers in Chronic HBeAg Negative HBV Infection. Genes. 2018;9:469.

    Not in our library10.3390/genes9100469

  151. 151.

    Hildt E., Hofschneider P.H. The PreS2 activators of the hepatitis B virus: Activators of tumour promoter pathways. Recent Results Cancer Res. 1998;154:315-329.

    Not in our library10.1007/978-3-642-46870-4_23

  152. 152.

    Liu P., Zhang H., Liang X., Ma H., Luan F., Wang B., Bai F., Gao L., Ma C. HBV preS2 promotes the expression of TAZ via miRNA-338-3p to enhance the tumorigenesis of hepatocellular carcinoma. Oncotarget. 2015;6:29048-29059.

    Not in our library10.18632/oncotarget.4804

  153. 153.

    Wang M.L., Wu D.B., Tao Y.C., Chen L.L., Liu C.P., Chen E.Q., Tang H. The truncated mutant HBsAg expression increases the tumorigenesis of hepatitis B virus by regulating TGF-β/Smad signaling pathway. Virol. J. 2018;15:61.

    Not in our library10.1186/s12985-018-0972-0

  154. 154.

    Song J., Zhang X., Ge Q., Yuan C., Chu L., Liang H.F., Liao Z., Liu Q., Zhang Z., Zhang B. CRISPR/Cas9-mediated knockout of HBsAg inhibits proliferation and tumorigenicity of HBV-positive hepatocellular carcinoma cells. J. Cell. Biochem. 2018;119:8419-8431.

    Not in our library10.1002/jcb.27050

  155. 155.

    Kanda T., Wu S., Sasaki R., Nakamura M., Haga Y., Jiang X., Nakamoto S., Yokosuka O. HBV Core Protein Enhances Cytokine Production. Diseases. 2015;3:213-220.

    Not in our library10.3390/diseases3030213

  156. 156.

    Wu S., Kanda T., Imazeki F., Nakamoto S., Tanaka T., Arai M., Roger T., Shirasawa H., Nomura F., Yokosuka O. Hepatitis B virus e antigen physically associates with receptor-interacting serine/threonine protein kinase 2 and regulates IL-6 gene expression. J. Infect. Dis. 2012;206:415-420.

    Not in our library10.1093/infdis/jis363

  157. 157.

    Chen M.T., Billaud J.N., Sällberg M., Guidotti L.G., Chisari F.V., Jones J., Hughes J., Milich D.R. A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen. Proc. Natl. Acad. Sci. USA. 2004;101:14913-14918.

    Not in our library10.1073/pnas.0406282101

  158. 158.

    Chen M., Sällberg M., Hughes J., Jones J., Guidotti L.G., Chisari F.V., Billaud J.N., Milich D.R. Immune tolerance split between hepatitis B virus precore and core proteins. J. Virol. 2005;79:3016-3027.

    Not in our library10.1128/jvi.79.5.3016-3027.2005

  159. 159.

    Yaginuma K., Kobayashi H., Kobayashi M., Morishima T., Matsuyama K., Koike K. Multiple integration site of hepatitis B virus DNA in hepatocellular carcinoma and chronic active hepatitis tissues from children. J. Virol. 1987;61:1808-1813.

    Not in our library10.1128/jvi.61.6.1808-1813.1987

  160. 160.

    Zhou Y.Z., Butel J.S., Li P.J., Finegold M.J., Melnick J.L. Integrated state of subgenomic fragments of hepatitis B virus DNA in hepatocellular carcinoma from mainland China. J. Natl. Cancer Inst. 1987;79:223-231.

    Not in our library

  161. 161.

    Kim C.M., Koike K., Saito I., Miyamura T., Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature. 1991;351:317-320.

    Not in our library10.1038/351317a0

  162. 162.

    Wollersheim M., Debelka U., Hofschneider P.H. A transactivating function encoded in the hepatitis B virus X gene is conserved in the integrated state. Oncogene. 1988;3:545-552.

    Not in our library

  163. 163.

    Kekulé A.S., Lauer U., Weiss L., Luber B., Hofschneider P.H. Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature. 1993;361:742-745.

    Not in our library10.1038/361742a0

  164. 164.

    Choi B.H., Choi M., Jeon H.Y., Rho H.M. Hepatitis B viral X protein overcomes inhibition of E2F1 activity by pRb on the human Rb gene promoter. DNA Cell Biol. 2001;20:75-80.

    Not in our library10.1089/104454901750070274

  165. 165.

    Staib F., Hussain S.P., Hofseth L.J., Wang X.W., Harris C.C. TP53 and liver carcinogenesis. Hum. Mutat. 2003;21:201-216.

    Not in our library10.1002/humu.10176

  166. 166.

    Cha M.Y., Kim C.M., Park Y.M., Ryu W.S. Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells. Hepatology. 2004;39:1683-1693.

    Not in our library10.1002/hep.20245

  167. 167.

    Longato L., de la Monte S., Kuzushita N., Horimoto M., Rogers A.B., Slagle B.L., Wands J.R. Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver. Hepatology. 2009;49:1935-1943.

    Not in our library10.1002/hep.22856

  168. 168.

    Keng V.W., Tschida B.R., Bell J.B., Largaespada D.A. Modeling hepatitis B virus X-induced hepatocellular carcinoma in mice with the Sleeping Beauty transposon system. Hepatology. 2011;53:781-790.

    Not in our library10.1002/hep.24091

  169. 169.

    Wang C., Yang W., Yan H.X., Luo T., Zhang J., Tang L., Wu F.Q., Zhang H.L., Yu L.X., Zheng L.Y., et al. Hepatitis B virus X (HBx) induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated HBx transgenic mice. Hepatology. 2012;55:108-120.

    Not in our library10.1002/hep.24675

  170. 170.

    Von Olshausen G., Quasdorff M., Bester R., Arzberger S., Ko C., van de Klundert M., Zhang K., Odenthal M., Ringelhan M., Niessen C.M., et al. Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion. Oncotarget. 2018;9:33947-33960.

    Not in our library10.18632/oncotarget.26103

  171. 171.

    Singh A.K., Swarnalatha M., Kumar V. c-ETS1 facilitates G1/S-phase transition by up-regulating cyclin E and CDK2 genes and cooperates with hepatitis B virus X protein for their deregulation. J. Biol. Chem. 2011;286:21961-21970.

    Not in our library10.1074/jbc.m111.238238

  172. 172.

    Luo L., Chen S., Gong Q., Luo N., Lei Y., Guo J., He S. Hepatitis B virus X protein modulates remodelling of minichromosomes related to hepatitis B virus replication in HepG2 cells. Int. J. Mol. Med. 2013;31:197-204.

    Not in our library10.3892/ijmm.2012.1165

  173. 173.

    Saeed U., Kim J., Piracha Z.Z., Kwon H., Jung J., Chwae Y.J., Park S., Shin H.J., Kim K. Parvulin 14 and parvulin 17 bind to HBx and cccDNA and upregulate HBV replication from cccDNA to virion in a HBx-dependent manner. J. Virol. 2019;93:e01840-18.

    Not in our library10.1128/jvi.01840-18

  174. 174.

    Swarnalatha M., Singh A.K., Kumar V. Promoter occupancy of MLL1 histone methyltransferase seems to specify the proliferative and apoptotic functions of E2F1 in a tumour microenvironment. J. Cell Sci. 2013;126:4636-4646.

    Not in our library10.1242/jcs.126235

  175. 175.

    Huang Y.H., Tseng Y.H., Lin W.R., Hung G., Chen T.C., Wang T.H., Lee W.C., Yeh C.T. HBV polymerase overexpression due to large core gene deletion enhances hepatoma cell growth by binding inhibition of microRNA-100. Oncotarget. 2016;7:9448-9461.

    Not in our library10.18632/oncotarget.7021

  176. 176.

    Chung H.J., Chen X., Yu Y., Lee H.K., Song C.H., Choe H., Lee S., Kim H.J., Hong S.T. A critical role of hepatitis B virus polymerase in cirrhosis, hepatocellular carcinoma, and steatosis. FEBS Open Bio. 2017;8:130-145.

    Not in our library10.1002/2211-5463.12357

  177. 177.

    Kakumu S., Okumura A., Ishikawa T., Yano M., Enomoto A., Nishimura H., Yoshioka K., Yoshika Y. Serum levels of IL-10, IL-15 and soluble tumour necrosis factor-alpha (TNF-alpha) receptors in type C chronic liver disease. Clin. Exp. Immunol. 1997;109:458-463.

    Not in our library10.1046/j.1365-2249.1997.4861382.x

  178. 178.

    Kanda T., Yokosuka O., Omata M. Hepatitis C virus and hepatocellular carcinoma. Biology. 2013;2:304-316.

    Not in our library10.3390/biology2010304

  179. 179.

    Braconi C., Valeri N., Gasparini P., Huang N., Taccioli C., Nuovo G., Suzuki T., Croce C.M., Patel T. Hepatitis C virus proteins modulate microRNA expression and chemosensitivity in malignant hepatocytes. Clin. Cancer Res. 2010;16:957-966.

    Not in our library10.1158/1078-0432.ccr-09-2123

  180. 180.

    Zhang Y., Wei W., Cheng N., Wang K., Li B., Jiang X., Sun S. Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology. 2012;56:1631-1640.

    Not in our library10.1002/hep.25849

  181. 181.

    Hsu S.H., Wang B., Kota J., Yu J., Costinean S., Kutay H., Yu L., Bai S., La Perle K., Chivukula R.R., et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J. Clin. Investig. 2012;122:2871-2883.

    Not in our library10.1172/jci63539

  182. 182.

    Zhao L., Li F., Taylor E.W. Can tobacco use promote HCV-induced miR-122 hijacking and hepatocarcinogenesis? Med. Hypotheses. 2013;80:131-133.

    Not in our library10.1016/j.mehy.2012.11.009

  183. 183.

    Salvi A., Abeni E., Portolani N., Barlati S., De Petro G. Human hepatocellular carcinoma cell-specific miRNAs reveal the differential expression of miR-24 and miR-27a in cirrhotic/non-cirrhotic HCC. Int. J. Oncol. 2013;42:391-402.

    Not in our library10.3892/ijo.2012.1716

  184. 184.

    Elfimova N., Sievers E., Eischeid H., Kwiecinski M., Noetel A., Hunt H., Becker D., Frommolt P., Quasdorff M., Steffen H.M., et al. Control of mitogenic and motogenic pathways by miR-198, diminishing hepatoma cell growth and migration. Biochim. Biophys. Acta. 2013;1833:1190-1198.

    Not in our library10.1016/j.bbamcr.2013.01.023

  185. 185.

    Thomas M., Deiters A. MicroRNA miR-122 as a therapeutic target for oligonucleotides and small molecules. Curr Med Chem. 2013;20:3629-3640.

    Not in our library10.2174/0929867311320290009

  186. 186.
    HCV core protein-induced down-regulation of microRNA-152 promoted aberrant proliferation by regulating Wnt1 in HepG2 cells. · 2014
    Not checked
  187. 187.

    Mukherjee A., Shrivastava S., Bhanja Chowdhury J., Ray R., Ray R.B. Transcriptional suppression of miR-181c by hepatitis C virus enhances homeobox A1 expression. J. Virol. 2014;88:7929-7940.

    Not in our library10.1128/jvi.00787-14

  188. 188.

    Xu G., Yang F., Ding C.L., Wang J., Zhao P., Wang W., Ren H. MiR-221 accentuates IFN׳s anti-HCV effect by downregulating SOCS1 and SOCS3. Virology. 2014;462–463:343-350.

    Not in our library10.1016/j.virol.2014.06.024

  189. 189.

    Pan L., Ren F., Rong M., Dang Y., Luo Y., Luo D., Chen G. Correlation between down-expression of miR-431 and clinicopathological significance in HCC tissues. Clin. Transl. Oncol. 2015;17:557-563.

    Not in our library10.1007/s12094-015-1278-y

  190. 190.

    El-Abd N.E., Fawzy N.A., El-Sheikh S.M., Soliman M.E. Circulating miRNA-122, miRNA-199a, and miRNA-16 as Biomarkers for Early Detection of Hepatocellular Carcinoma in Egyptian Patients with Chronic Hepatitis C Virus Infection. Mol. Diagn. Ther. 2015;19:213-220.

    Not in our library10.1007/s40291-015-0148-1

  191. 191.

    Devhare P.B., Steele R., Di Bisceglie A.M., Kaplan D.E., Ray R.B. Differential Expression of MicroRNAs in Hepatitis C Virus-Mediated Liver Disease Between African Americans and Caucasians: Implications for Racial Health Disparities. Gene Expr. 2017;17:89-98.

    Not in our library10.3727/105221616x693594

  192. 192.

    Shiu T.Y., Shih Y.L., Feng A.C., Lin H.H., Huang S.M., Huang T.Y., Hsieh C.B., Chang W.K., Hsieh T.Y. HCV core inhibits hepatocellular carcinoma cell replicative senescence through downregulating microRNA-138 expression. J. Mol. Med. 2017;95:629-639.

    Not in our library10.1007/s00109-017-1518-4

  193. 193.

    Shaker O., Alhelf M., Morcos G., Elsharkawy A. miRNA-101-1 and miRNA-221 expressions and their polymorphisms as biomarkers for early diagnosis of hepatocellular carcinoma. Infect. Genet. Evol. 2017;51:173-181.

    Not in our library10.1016/j.meegid.2017.03.030

  194. 194.

    Shehata R.H., Abdelmoneim S.S., Osman O.A., Hasanain A.F., Osama A., Abdelmoneim S.S., Toraih E.A. Deregulation of miR-34a and Its Chaperon Hsp70 in Hepatitis C virus-Induced Liver Cirrhosis and Hepatocellular Carcinoma Patients. Asian Pac. J. Cancer Prev. 2017;18:2395-2401.

    Not in our library10.22034/apjcp.2017.18.9.2395

  195. 195.

    Sur S., Sasaki R., Devhare P., Steele R., Ray R., Ray R.B. Association between MicroRNA-373 and Long Noncoding RNA NORAD in Hepatitis C Virus-Infected Hepatocytes Impairs Wee1 Expression for Growth Promotion. J. Virol. 2018;92:e01215-18.

    Not in our library10.1128/jvi.01215-18

  196. 196.

    Rashad N.M., El-Shal A.S., Shalaby S.M., Mohamed S.Y. Serum miRNA-27a and miRNA-18b as potential predictive biomarkers of hepatitis C virus-associated hepatocellular carcinoma. Mol. Cell. Biochem. 2018;447:125-136.

    Not in our library10.1007/s11010-018-3298-8

  197. 197.

    Hou W., Bonkovsky H.L. Non-coding RNAs in hepatitis C-induced hepatocellular carcinoma: Dysregulation and implications for early detection, diagnosis and therapy. World J. Gastroenterol. 2013;19:7836-7845.

    Not in our library10.3748/wjg.v19.i44.7836

  198. 198.

    Zhang H., Zhu C., Zhao Y., Li M., Wu L., Yang X., Wan X., Wang A., Zhang M.Q., Sang X., et al. Long non-coding RNA expression profiles of hepatitis C virus-related dysplasia and hepatocellular carcinoma. Oncotarget. 2015;6:43770-43778.

    Not in our library10.18632/oncotarget.6087

  199. 199.

    Kamel M.M., Matboli M., Sallam M., Montasser I.F., Saad A.S., El-Tawdi A.H.F. Investigation of long noncoding RNAs expression profile as potential serum biomarkers in patients with hepatocellular carcinoma. Transl. Res. 2016;168:134-145.

    Not in our library10.1016/j.trsl.2015.10.002

  200. 200.

    Fu N., Niu X., Wang Y., Du H., Wang B., Du J., Li Y., Wang R., Zhang Y., Zhao S., et al. Role of LncRNA-activated by transforming growth factor beta in the progression of hepatitis C virus-related liver fibrosis. Discov. Med. 2016;22:29-42.

    Not in our library

  201. 201.

    Kanda T., Tada M., Imazeki F., Yokosuka O., Nagao K., Saisho H. 5-aza-2’-deoxycytidine sensitizes hepatoma and pancreatic cancer cell lines. Oncol. Rep. 2005;14:975-979.

    Not in our library10.3892/or.14.4.975

  202. 202.

    Ray R.B., Lagging L.M., Meyer K., Ray R. Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J. Virol. 1996;70:4438-4443.

    Not in our library10.1128/jvi.70.7.4438-4443.1996

  203. 203.

    Moriya K., Fujie H., Shintani Y., Yotsuyanagi H., Tsutsumi T., Ishibashi K., Matsuura Y., Kimura S., Miyamura T., Koike K. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat. Med. 1998;4:1065-1067.

    Not in our library10.1038/2053

  204. 204.

    Kanda T., Steele R., Ray R., Ray R.B. Hepatitis C virus core protein augments androgen receptor-mediated signaling. J. Virol. 2008;82:11066-11072.

    Not in our library10.1128/jvi.01300-08

  205. 205.

    Ghosh A.K., Majumder M., Steele R., Meyer K., Ray R., Ray R.B. Hepatitis C virus NS5A protein protects against TNF-alpha mediated apoptotic cell death. Virus Res. 2000;67:173-178.

    Not in our library10.1016/s0168-1702(00)00141-6

  206. 206.

    Majumder M., Ghosh A.K., Steele R., Ray R., Ray R.B. Hepatitis C virus NS5A physically associates with p53 and regulates p21/waf1 gene expression in a p53-dependent manner. J. Virol. 2001;75:1401-1407.

    Not in our library10.1128/jvi.75.3.1401-1407.2001

  207. 207.

    Imazeki F., Yokosuka O., Fukai K., Kanda T., Kojima H., Saisho H. Prevalence of diabetes mellitus and insulin resistance in patients with chronic hepatitis C: Comparison with hepatitis B virus-infected and hepatitis C virus-cleared patients. Liver Int. 2008;28:355-362.

    Not in our library10.1111/j.1478-3231.2007.01630.x

  208. 208.

    Neuschwander-Tetri B.A., Clark J.M., Bass N.M., Van Natta M.L., Unalp-Arida A., Tonascia J., Zein C.O., Brunt E.M., Kleiner D.E., McCullough A.J., et al. NASH Clinical Research Network. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010;52:913-924.

    Not in our library10.1002/hep.23784

  209. 209.

    Haga Y., Kanda T., Sasaki R., Nakamura M., Nakamoto S., Yokosuka O. Nonalcoholic fatty liver disease and hepatic cirrhosis: Comparison with viral hepatitis-associated steatosis. World J. Gastroenterol. 2015;21:12989-12995.

    Not in our library10.3748/wjg.v21.i46.12989

  210. 210.

    Kawaguchi T., Yoshida T., Harada M., Hisamoto T., Nagao Y., Ide T., Taniguchi E., Kumemura H., Hanada S., Maeyama M., et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am. J. Pathol. 2004;165:1499-1508.

    Not in our library10.1016/s0002-9440(10)63408-6

  211. 211.

    Miyamoto H., Moriishi K., Moriya K., Murata S., Tanaka K., Suzuki T., Miyamura T., Koike K., Matsuura Y. Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J. Virol. 2007;81:1727-1735.

    Not in our library10.1128/jvi.01683-06

  212. 212.

    Banerjee S., Saito K., Ait-Goughoulte M., Meyer K., Ray R.B., Ray R. Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J. Virol. 2008;82:2606-2612.

    Not in our library10.1128/jvi.01672-07

  213. 213.

    Banerjee A., Meyer K., Mazumdar B., Ray R.B., Ray R. Hepatitis C virus differentially modulates activation of forkhead transcription factors and insulin-induced metabolic gene expression. J. Virol. 2010;84:5936-5946.

    Not in our library10.1128/jvi.02344-09

  214. 214.

    Bose S.K., Shrivastava S., Meyer K., Ray R.B., Ray R. Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. J. Virol. 2012;86:6315-6322.

    Not in our library10.1128/jvi.00050-12

  215. 215.

    Tanaka S., Wands J.R. Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta1-induced apoptosis. Cancer Res. 1996;56:3391-3394.

    Not in our library

  216. 216.

    Qadri I., Choudhury M., Rahman S.M., Knotts T.A., Janssen R.C., Schaack J., Iwahashi M., Puljak L., Simon F.R., Kilic G., et al. Increased phosphoenolpyruvate carboxykinase gene expression and steatosis during hepatitis C virus subgenome replication: Role of nonstructural component 5A and CCAAT/enhancer-binding protein β. J. Biol. Chem. 2012;287:37340-37351.

    Not in our library10.1074/jbc.m112.384743

  217. 217.

    Parvaiz F., Manzoor S., Iqbal J., McRae S., Javed F., Ahmed Q.L., Waris G. Hepatitis C virus nonstructural protein 5A favors upregulation of gluconeogenic and lipogenic gene expression leading towards insulin resistance: A metabolic syndrome. Arch. Virol. 2014;159:1017-1025.

    Not in our library10.1007/s00705-013-1892-3

  218. 218.

    Parvaiz F., Manzoor S., Iqbal J., Sarkar-Dutta M., Imran M., Waris G. Hepatitis C virus NS5A promotes insulin resistance through IRS-1 serine phosphorylation and increased gluconeogenesis. World J. Gastroenterol. 2015;21:12361-12369.

    Not in our library10.3748/wjg.v21.i43.12361

  219. 219.

    Kwon Y.C., Bose S.K., Steele R., Meyer K., Di Bisceglie A.M., Ray R.B., Ray R. Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes. J. Virol. 2015;89:11549-11556.

    Not in our library10.1128/jvi.01946-15

  220. 220.

    Kwon Y.C., Sasaki R., Meyer K., Ray R. Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis. J. Virol. 2017;91:e01235-17.

    Not in our library10.1128/jvi.01235-17

  221. 221.

    Uthaya Kumar D.B., Chen C.L., Liu J.C., Feldman D.E., Sher L.S., French S., DiNorcia J., French S.W., Naini B.V., Junrungsee S., et al. TLR4 Signaling via NANOG Cooperates with STAT3 to Activate Twist1 and Promote Formation of Tumor-Initiating Stem-Like Cells in Livers of Mice. Gastroenterology. 2016;150:707-719.

    Not in our library10.1053/j.gastro.2015.11.002

  222. 222.
    Systemic Therapy for Hepatocellular Carcinoma: Latest Advances · 2018
    No notice
  223. 223.

    Okazaki T., Honjo T. PD-1 and PD-1 ligands: From discovery to clinical application. Int. Immunol. 2007;19:813-824.

    Not in our library10.1093/intimm/dxm057

  224. 224.

    Iwai Y., Ishida M., Tanaka Y., Okazaki T., Honjo T., Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. USA. 2002;99:12293-12297.

    Not in our library10.1073/pnas.192461099

  225. 225.

    Leach D.R., Krummel M.F., Allison J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734-1736.

    Not in our library10.1126/science.271.5256.1734

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