Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma

Hoshida, Yujin; Fuchs, Bryan C.; Bardeesy, Nabeel; Baumert, Thomas F.; Chung, Raymond T.

doi:10.1016/j.jhep.2014.07.010

Cited by 198 publications

(191 citation statements)

References 171 publications

(176 reference statements)

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“…Progression of chronic hepatitis C to poor-prognosis liver disease and HCC is a multifactorial process that involves persistent hepatic inflammation, progressive liver fibrogenesis, development of neoplastic clones, and finally establishment of a carcinogenic tissue microenvironment (63). Since they are central players under both physiological and pathological conditions, miRNAs most likely contribute to HCV-driven liver disease (3,8).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Bandiera

Pernot

Saghire

et al. 2016

J Virol

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Hepatitis C virus (HCV)-induced chronic liver disease is a leading cause of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in homeostasis within the liver, and deregulation of miRNAs has been associated with liver disease, including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here we combined a hepatocyte-like cell-based model system, high-throughput small RNA sequencing, computational analysis, and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least 2-fold, including miRNAs that were previously described to target genes associated with inflammation, fibrosis, and cancer development. Further investigation demonstrated that the miR-146a-5p level was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes, as well as in liver tissue from HCV-infected patients. Genomewide microarray and computational analyses indicated that miR-146a-5p overexpression modulates pathways that are related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p has a positive impact on late steps of the viral replication cycle, thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease. IMPORTANCEHCV is a leading cause of chronic liver disease and cancer. However, how HCV induces liver cancer remains poorly understood. There is accumulating evidence that a viral cure does not eliminate the risk for HCC development. Thus, there is an unmet medical need to develop novel approaches to predict and prevent virus-induced HCC. miRNA expression is known to be deregulated in liver disease and cancer. Furthermore, miRNAs are essential for HCV replication, and HCV infection alters miRNA expression. However, how miRNAs contribute to HCV-driven pathogenesis remains elusive. Here we show that HCV induces miRNAs that may contribute to liver injury and carcinogenesis. The miR-146a-5p level was consistently increased in different cell-based models of HCV infection and in HCV patient-derived liver tissue. Furthermore, miR-146a-5p increased HCV infection. Collectively, our data are relevant to understanding viral pathogenesis and may open perspectives for novel biomarkers and prevention of virus-induced liver disease and HCC. H epatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC) worldw...

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Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Bandiera

Pernot

Saghire

et al. 2016

J Virol

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“…Sustained virologic response (SVR) correlated with disease severity at the point of treatment (4). The eradication of HCV by recently emerged direct-acting antivirals (DAAs) does not completely eliminate the risk of HCC (5,6). A strong link exists between chronic HCV infection and HCC, although the mechanism for disease promotion remains poorly understood.…”

mentioning

confidence: 99%

Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes

Kwon

Bose

Steele

et al. 2015

J Virol

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We have previously reported that hepatitis C virus (HCV) infection of primary human hepatocytes (PHH IMPORTANCEHCV infection may develop into HCC as an end-stage liver disease. We focused on understanding the mechanism for the risk of HCC from chronic HCV infection and identified targets for treatment. HCV-infected primary and transformed human hepatocytes (PHH or THH) generated CSC. HCV-induced spheres were highly sensitive to cell death from sorafenib and stattic treatment. Thus, our study is highly significant for HCV-associated HCC, with the potential for developing a target-specific strategy for improved therapies.

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“…Furthermore, typical of HCV-related HCCs is the expression of the liver-specific microRNA (miR)-122, a host cell factor that is necessary for HCV replication and has also relevant tumor-suppressor properties in the liver [59]. In addition, the artificial overexpression of HCV proteins -including core, NS3 and NS5A -causes cellular proliferation and tumor formation in mice, thus suggesting a potential direct contribution in activating oncogenic molecular pathways [60][61][62][63]. Therefore, the replicative cycle of HCV seems to be directly linked to procarcinogenic cellular phenomena [53].…”

Section: Hcv-induced Carcinogenesis and Residual Risk Of Hcc After Svrmentioning

confidence: 99%

“…As a consequence, DNA damage may occur also in uninfected liver cells [64]. All in all, HCV proteins -both directly and indirectly -promote immune evasion, cellular deregulation and inflammation, thus producing fibrogenesis, oxidative stress, DNA damage and genetic instability: these phenomena altogether are capable to create and expand tumor-initiating/cancer stem cells [63].…”

Section: Hcv-induced Carcinogenesis and Residual Risk Of Hcc After Svrmentioning

confidence: 99%

Residual Risk of Hepatocellular Carcinoma After HCV Eradication: more than meets the eye

Macaluso

Calvaruso

2015

Future Microbiol.

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Eradication of HCV in patients with advanced liver fibrosis or cirrhosis reduces, but does not altogether abolish, the risk of development of hepatocellular carcinoma. The reasons underlying this residual risk remain elusive. Even if HCV clearance eliminates its direct and indirect carcinogenic effects, the persistence of cirrhosis and the possible coexistence of metabolic factors (diabetes, obesity and insulin resistance) and of alcohol abuse can promote the development of hepatocellular carcinoma acting as autonomous, nonviral carcinogenic factors. Lessons learned in the IFN era may still assist in predicting the forthcoming scenario, when IFN-free regimens will obtain high rates of viral clearance even at the most advanced stages of liver disease. KeywordsHepatocellular carcinoma (HCC) is a challenging malignancy of global importance, being the second cause of cancer-related death worldwide [1]. The majority of HCCs occur in the context of chronic infection with HBV and HCV, and the cancer risk is directly related to the histological and clinical stage of the underlying liver disease [2]. In particular, HCV infection stands today as the leading risk factor for HCC in many industrialized countries [3], occurring at a rate between 3 and 8%, according to the geographic area, in patients with HCV-related cirrhosis [4]. On these assumptions, prevention of population exposure to HCV can be regarded as the most effective tool to reduce liver-related mortality from HCC due to chronic HCV infection. In the HCV scenario, where an effective vaccine is not currently available, antiviral treatments have stood as the real backbone of prophylaxis strategy in the prevention of HCC, of course together with all procedures implemented to prevent HCV transmission [5].However, the evidence that patients with chronic hepatitis C (CHC) are completely protected against occurrence of HCC by successful IFN-based treatments is controversial, mainly due to methodological limitations of available literature. All in all, HCC risk seems to be sharply attenuated, although not completely eliminated -especially in patients with advanced fibrosis -following eradication of HCV infection, and the causes for this residual HCC risk in patients who achieved a sustained virological response (SVR) remain receding. Moreover, the intrinsic limitations of the use of IFN to patients with less advanced liver disease have curtailed the potential benefit, due to the fact that HCC in HCV cirrhosis becomes more prevalent at the more advanced stages of liver disease.In this review, we discuss the available clinical evidence of the role of antiviral treatment against chronic HCV infection for the prevention of HCC, and the residual risk existing in patients successfully treated. In addition, we focus on the molecular mechanisms that might explain the pathophysiological rationale of the reduction, but not elimination, of HCC risk after HCV eradication. The lesson from the IFN era may be extremely useful to predict the near-future scenario, when For repri...

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Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma

Cited by 198 publications

References 171 publications

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes

Residual Risk of Hepatocellular Carcinoma After HCV Eradication: more than meets the eye

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