Hepatitis B virus and hepatocellular carcinoma

Arbuthnot, Patrick; Kew, Michael C.

doi:10.1111/j.1365-2613.2001.iep178.x

Cited by 262 publications

(66 citation statements)

References 222 publications

(271 reference statements)

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“…The epidemiological evidence linking HBV infection to HCC is very strong, and despite the mechanisms underlying HBV-associated carcinogenesis remain to be fully defined, a growing number of studies support a direct role of HBV in the process (2)(3)(4)(5). The HBV-encoded regulatory protein hepatitis B virus X protein (HBx) is thought to contribute to HBV oncogenicity (5,6).…”

Section: H Epatitis B Virus (Hbv) Infection Is a Major Health Problemmentioning

confidence: 99%

Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function

Belloni

Pollicino

Nicola

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

435

482

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HBV cccDNA, the template for transcription of all viral mRNAs, accumulates in the nucleus of infected cells as a stable episome organized into minichromosomes by histones and non-histone viral and cellular proteins. Using a cccDNA-specific chromatin immunoprecipitation (ChIP)-based quantitative assay, we have previously shown that transcription of the HBV minichromosome is regulated by epigenetic changes of cccDNA-bound histones and that modulation of the acetylation status of cccDNA-bound H3/H4 histones impacts on HBV replication. We now show that the cellular histone acetyltransferases CBP, p300, and PCAF/GCN5, and the histone deacetylases HDAC1 and hSirt1 are all recruited in vivo onto the cccDNA. We also found that the HBx regulatory protein produced in HBV replicating cells is recruited onto the cccDNA minichromosome, and the kinetics of HBx recruitment on the cccDNA parallels the HBV replication. As expected, an HBV mutant that does not express HBx is impaired in its replication, and exogenously expressed HBx transcomplements the replication defects. p300 recruitment is severely impaired, and cccDNA-bound histones are rapidly hypoacetylated in cells replicating the HBx mutant, whereas the recruitment of the histone deacetylases hSirt1 and HDAC1 is increased and occurs at earlier times. Finally, HBx mutant cccDNA transcribes significantly less pgRNA. Altogether our results further support the existence of a complex network of epigenetic events that influence cccDNA function and HBV replication and identify an epigenetic mechanism (i.e., to prevent cccDNA deacetylation) by which HBx controls HBV replication.histone acetylation ͉ HATs ͉ HDACs H epatitis B virus (HBV) infection is a major health problem, with Ϸ400 million people chronically infected worldwide who are at high risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) (1). The epidemiological evidence linking HBV infection to HCC is very strong, and despite the mechanisms underlying HBV-associated carcinogenesis remain to be fully defined, a growing number of studies support a direct role of HBV in the process (2-5). The HBV-encoded regulatory protein hepatitis B virus X protein (HBx) is thought to contribute to HBV oncogenicity (5, 6). HBx transforms SV40-immortalized murine hepatocytes, induces cell cycle progression within the regenerating liver, causes liver cancer in some transgenic mice, and acts as a cofactor to accelerate cancer development in other mouse models (6-11). HBx is a 154-amino acid protein with an N-terminal negative regulatory domain and C-terminal transactivation or coactivation domain that has been detected both in the cytoplasm and in the nuclei of infected hepatocytes (6,12,13). Studies in transfected cells have shown that HBx expression affects several cellular functions such as cytoplasmic calcium regulation, cell signaling, transcription, cell proliferation, DNA repair, and apoptosis (11, 13-16). To perform its multiple functions, HBx interacts with many cellular partners including the tumor suppressor p53,...

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Section: H Epatitis B Virus (Hbv) Infection Is a Major Health Problemmentioning

confidence: 99%

Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function

Belloni

Pollicino

Nicola

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

435

482

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“…Most liver cancers are hepatocellular carcinomas (HCC), which have unique epidemiologic features with dynamic temporal trends, and vary in different geographic regions, racial and ethnic group, sex and risk factors. [1][2][3] Although its hepatocarcinogenesis is not clearly illustrated, chronic active hepatitis is recognized as the major risk factor for HCC, and is accompanied by liver cell necrosis, inflammation, cytokine abnormal synthesis and fibrosis. The most common condition associated with hepatocarcinogenesis is cirrhosis, which develops after a latency of 20-40 years of chronic liver disease.…”

mentioning

confidence: 99%

Induction of liver fibrosis in a murine hepatoma model by thioacetamide is associated with enhanced tumor growth and suppressed antitumor immunity

Yang

Chang

Lei

2010

Laboratory Investigation

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Liver cirrhosis and hepatocellular carcinomas are two major causes of morbidity and mortality worldwide, and can synergistically interact to expedite the tumor progression. How fibrosis promotes the hepatoma growth remains completely unexplained. Using an in situ murine hepatoma model together with fibrosis induction by thioacetamide (TAA), the hepatoma growth and the immune factors in the fibrotic liver were analyzed. We found that TAA-fibrosis induction enhanced hepatoma cell growth in the liver and increased the mortality of hepatoma-bearing mice. The tumor-infiltrating CD4 þ or CD8 þ T cells are downregulated by fibrosis induction. The Foxp3 þ regulatory T cells (Treg) cells were induced. We conclude that fibrosis induction causes further immunosuppression, in which Treg cells exert a downregulation effect on the antitumor immunity.

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“…The detection and validation of new HBV biomarkers offers to be an important contribution to attain this goal. The development of new biomarkers for predicting an individual's risk for HCC after HBV infection is predicated upon an understanding of the molecular pathways through which the virus mediates its effects (4,12,27). The pathobiology of HBV infection is also modulated through the selection and expression of a number of common viral mutants that affect a number of key viral proteins (28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

“…The HBV genome encodes its essential genes with overlapping openreading frames; therefore, a mutation in the HBV genome can alter the expression of multiple proteins. In many cases of HCC in China and Africa, a double mutation in the HBV genome, an adenine to thymine transversion at nucleotide 1762, and a guanine to adenine transition at nucleotide 1764 (1762 T / 1764 A ), has been found in tumors (12)(13)(14). The molecular basis for the formation of these nucleotide changes and the temporal relation for HBV infection is still a source of active investigation.…”

Section: Introductionmentioning

confidence: 99%

Acceleration to Death from Liver Cancer in People with Hepatitis B Viral Mutations Detected in Plasma by Mass Spectrometry

Chen

Kuang

Egner

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Liver cancer is the leading cause of cancer death in many regions of the world. With the goal to discover biomarkers that reflect subsets of high-risk individuals and their prognosis, we nested our study in a male cohort of 5,581 hepatitis B surface antigen carriers in Qidong, People's Republic of China, who were recruited starting in 1989. By December 2003, 667 liver cancer cases were diagnosed in this group and plasma samples collected at the initial screening at enrollment were available in 515 cases who had succumbed to liver cancer. Hepatitis B virus (HBV) DNA could be isolated in 355 (69%) of these samples. In 14%, 15%, 19%, 31%, and 22%, screening took place at V1.5, 1.51 to 3, 3.01 to 5, 5.01 to 9, and >9 years before death, respectively; and 39% died at age below 45 years. The relation between mutations in HBV and time to death were determined by logistic regression for the odds of mutation and by survival analyses methods with age as the time scale. In 279 (79%) of these individuals, the samples contained a two-nucleotide 1762 T /1764 A HBV mutation. Sixteen samples lacking the 1762 T /1764 A mutation had novel mutations elsewhere in the 1761 to 1767 region of the HBV genome. There was a statistically significant difference (P = 0.012) for the high prevalence of the HBV mutations in the men who died from hepatocellular carcinoma under the age of 45 years relative to those who died after 55 years of age and HBV mutations accelerated death (relative hazard, 1.40; 95% confidence interval, 1.06-1.85) and that the effect was attenuated by age from 2.04 for age 35 years to 1.0 for age 65 years with the 90% confidence band being above 1 for ages <50 years. These findings provide a conceptual framework to explain the acceleration of mortality in individuals infected with HBV. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1213 -8)

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Hepatitis B virus and hepatocellular carcinoma

Cited by 262 publications

References 222 publications

Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function

Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function

Induction of liver fibrosis in a murine hepatoma model by thioacetamide is associated with enhanced tumor growth and suppressed antitumor immunity

Acceleration to Death from Liver Cancer in People with Hepatitis B Viral Mutations Detected in Plasma by Mass Spectrometry

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