The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma

Guerrero, Rubén Bonilla; Roberts, Lewis R.

doi:10.1016/j.jhep.2005.02.005

Cited by 184 publications

(149 citation statements)

References 128 publications

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“…Although the underlying causes of HBVassociated HCC remain incompletely understood, three mechanisms that are not mutually exclusive have been proposed as contributors to the development of HBV-associated HCC: recurrent immune-mediated destruction of HBV-infected hepatocytes followed by compensatory liver regeneration; integration of HBV DNA into the host genome, which could alter the expression of cellular factors and, in turn, the control of normal cell functions; and modulation of hepatocyte physiology by HBV proteins such as HBx (8,(76)(77)(78)(79). Although HBx is directly oncogenic in some HBx-transgenic mice (80,81), many studies suggest that HBx has a cofactor role in hepatocyte transformation (11,(82)(83)(84).…”

Section: Discussionmentioning

confidence: 99%

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

Rawat

Bouchard

2015

J Virol

112

126

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Chronic infection with hepatitis B virus (HBV) is a risk factor for developing liver diseases such as hepatocellular carcinoma (HCC). HBx is a multifunctional protein encoded by the HBV genome; HBx stimulates HBV replication and is thought to play an important role in the development of HBV-associated HCC. HBx can activate the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in some cell lines; however, whether HBx regulates PI3K/AKT signaling in normal hepatocytes has not been evaluated. In studies described here, we assessed HBx activation of PI3K/AKT signaling in an ex vivo model of cultured primary hepatocytes and determined how this HBx activity affects HBV replication. We report that HBx activates AKT in primary hepatocytes and that the activation of AKT decreases HBV replication and HBV mRNA and core protein levels. We show that the transcription factor hepatocyte nuclear factor 4␣ (HNF4␣) is a target of HBx-regulated AKT, and we link HNF4␣ to HBx-regulated AKT modulation of HBV transcription and replication. Although we and others have shown that HBx stimulates and is likely required for HBV replication, we now report that HBx also activates signals that can diminish the overall level of HBV replication. While this may seem counterintuitive, we show that an important effect of HBx activation of AKT is inhibition of apoptosis. Consequently, our studies suggest that HBx balances HBV replication and cell survival by stimulating signaling pathways that enhance hepatocyte survival at the expense of higher levels of HBV replication. IMPORTANCE Chronic hepatitis B virus (HBV) infection is Chronic infection with hepatitis B virus (HBV) remains a major global health problem. Despite the availability of effective HBV vaccines, there are ϳ350 million people worldwide who are chronically infected with HBV. Chronic HBV infection is the major cause of the development of hepatocellular carcinoma (HCC) (1). The level of HBV replication in a chronically HBV-infected individual can vary throughout the course of the infection, and the rise and fall of HBV replication during a chronic infection may affect disease progression (2, 3). There are limited therapeutic options for treating a chronic HBV infection, and the emergence of HBV mutants that are resistant to available therapies is common. Moreover, available anti-HBV drugs typically do not completely eliminate HBV in chronically infected individuals due to the presence and stability of covalently closed circular DNA (cccDNA), a replicative intermediate of HBV that is localized to the nucleus of HBV-infected hepatocytes (4-7). Consequently, there is continued interest in understanding the mechanisms that regulate HBV replication and could serve as potential therapeutic targets.HBV is an enveloped, partially double-stranded DNA virus that belongs to the Hepadnaviridae family of viruses (8). Although HBV is a DNA virus, it replicates through reverse transcription of an RNA intermediate. HBV replication occurs within the viral capsid in the cytosol of hepa...

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Section: Discussionmentioning

confidence: 99%

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

Rawat

Bouchard

2015

J Virol

112

126

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“…An estimated 0.1% of individuals with HBV without cirrhosis develop HCC [9] , likely due to the carcinogenic effect of the virus [10] . HCV is described in most studies as being of low potential for developing HCC in the absence of cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

“…In Western countries, the prevalence of hepatocellular carcinoma in non-cirrhosis (HCC-NC) patients was estimated in 15% to 20% of cases [6][7][8] , and the most common risk factors were HBV and HCV. However, a majority of the information was obtained from Asia and Africa, where the prevalence of hepatitis B and C viral infections is also elevated [9][10][11] . NASH is considered a relevant risk factor of liver disease worldwide [12] .…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular carcinoma in patients without cirrhosis: relevance and clinical characteristics

Carvalho¹,

Fonseca²,

Cotrim³

2018

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Aim: The present study evaluated the frequency of hepatocellular carcinoma (HCC) in patients without cirrhosis.Methods: HCC patients were recruited from two reference centers for liver disease in Northeast Brazil from 2010 to 2016. The diagnosis of HCC and cirrhosis was based on international criteria. Results:A total of 169 patients were included, and 16% (27) of the patients did not have hepatocellular carcinoma in non-cirrhosis (HCC-NC). The mean age of HCC-NC was 64.4 ± 11.3 years, and 74.1% of the patients were male. The main risk factors were hepatitis C virus (HCV) in 29.6% (8), nonalcoholic steatohepatitis (NASH) in 14.8% (4) and hepatitis B virus (HBV) in 11.1% (3). Histological HCC diagnosis was performed in 81.5% (22) of the patients, and in 18.5% (5) of these patients, the diagnosis was performed by ultrasonography, computed tomography or nuclear magnetic resonance imaging methods. Single nodules were found in 56% of HCC-NC (14) when assessed by imaging methods. Conclusion:The frequency of HCC-NC was elevated and more common in males. HCV, NASH and HBV were the most frequent risk factors. These data contribute to discussion on future protocols and criteria for the early diagnosis and treatment of HCC in patients with chronic liver disease without cirrhosis.

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“…In HCC, in addition to the long-lasting hepatitis produced by a chronic infection, the HBV may exert a direct oncogenic role through several different mechanisms, including viral DNA integration into the host genome and production of proteins with pro-oncogenic properties [1,2] . HBV DNA integration occurs randomly in the context of the human genome and may involve multiple sites located on different chromosomes [2,23,24] . In cases similar to this one, the HBV may promote liver cell transformation and cancer progression even independently of cirrhosis development [1,2] .…”

Section: A B C Dmentioning

confidence: 99%

Hepatocellular carcinoma with concomitant hepatic angiomyolipoma and cavernous hemangioma in one patient

Ge¹,

Zeng²,

Sujie³

et al. 2015

WJG

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The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma

Cited by 184 publications

References 128 publications

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

Hepatocellular carcinoma in patients without cirrhosis: relevance and clinical characteristics

Hepatocellular carcinoma with concomitant hepatic angiomyolipoma and cavernous hemangioma in one patient

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