Transcriptional repression of p21waf1 promoter by hepatitis B virus X protein via a p53-independent pathway

Ahn, Ji Young; Chung, Eun Young; Kwun, Hyun Jin; Jang, Kyung Lib

doi:10.1016/s0378-1119(01)00604-7

Cited by 51 publications

(49 citation statements)

References 23 publications

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“…19,20 We have previously hypothesized that in an organ like the liver, in which hepatocytes usually are in a quiescent state, a persistently elevated proliferative activity would enhance tumor development not only favoring genomic mutations but also inducing immunosuppression of the locoregional immune system. Indeed, the latter mechanism would act by enabling mutated cells to escape immunosurveillance.…”

Section: Discussionmentioning

confidence: 99%

Influence of Ursodeoxycholate–Enriched Diet on Liver Tumor Growth in Hbv Transgenic Mice

Barone¹,

Maiorano

Ladisa³

et al. 2003

Hepatology

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Hepatitis B virus (HBV) transgenic mice (official designation, Tg [Alb-1 HBV] Bri 44) invariably develop macroscopically evident tumors within the 20th month of life. Sustained proliferative activity seems to play an important role in the development of these lesions. We previously showed that ursodeoxycholate (UDC) stimulates hepatocyte proliferation in various experimental settings. Herein, we tested the assumption that biological factors able to further increase liver cell proliferation, such as UDC, could accelerate tumor development in this animal model. For this study, 22 eight-week-old male transgenic mice were divided into 2 groups; 11 animals received a standard diet, and 11 received a UDC-enriched diet. The 2 groups were further divided into 2 subgroups of 5 and 6 animals each and were sacrificed at 3 and 15 months of age, respectively. These different times were chosen to exclude diet-related toxicity (in 3-month-old mice) and evaluate tumor growth (in 15-month-old mice). In addition, hepatocyte proliferation was assessed in all animals. In 3-month-old mice receiving UDC, cholestatic and cytolytic indices as well as liver histology were comparable to those in controls. At 15 months, all UDC-treated mice showed large multinodular tumors whereas only 33% of controls developed smaller uninodular neoplasms. Hepatocyte proliferation was increased in all animals receiving UDC compared with controls. In conclusion, the increase in serum UDC (undetectable in mice fed a standard diet), in the absence of any toxic effect on the liver, suggests the involvement of this bile salt in the stimulation of hepatocyte proliferation and tumor growth. (HEPATOLOGY 2003;37:880-886.) T ransgenic mice with hepatitis B virus (HBV) sequences encoding for viral proteins pre-S, S, and X (official designation, Tg [Alb-1 HBV] Bri 44) develop progressive hepatocyte damage due to intracellular accumulation of these proteins. 1-5 During the first months of life, the hepatic damage consists of degenerative alterations. 2 Later, an active inflammatory response commences that induces a marked damage-related compensatory proliferative reaction. 3,5 Such a condition should be considered precancerous because it is constantly followed after the 8th to 9th month of life by the development of dysplastic hepatic lesions 3,4 that progress to overt liver cancer after the 12th month of life. 3 The progressive growth of these neoplastic lesions leads to macroscopic nodules that are invariably observed in all transgenic mice within the 20th month of life. 4 Interestingly, these transgenic mice, harboring hepatocellular carcinomas, do not manifest any specific alteration of known oncogenes or tumor suppressor genes at any stage of neoplastic transformation. 6 It has therefore been suggested that the damage-related sustained proliferative activity observed in the liver of these animals could play an important role in tumor development. 5 We have already shown that bile salts can stimulate proliferation in cultured hepatocytes and augment the regene...

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Section: Discussionmentioning

confidence: 99%

Influence of Ursodeoxycholate–Enriched Diet on Liver Tumor Growth in Hbv Transgenic Mice

Barone¹,

Maiorano

Ladisa³

et al. 2003

Hepatology

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“…There are also some reported studies examining the relationship between HBV and p21. Some reports have shown that the HBx gene exerts oncogenic activity by suppressing p21 expression [31,32] and that…”

Section: Hcc Hbx and P21mentioning

confidence: 99%

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Ohkoshi

Yano

Matsuda

2015

WJG

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A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention. Core tip: A well-known tumor suppressor, p21, can act paradoxically by promoting tumor growth, depending on its subcellular localization. Nuclear p21 may inhibit cell proliferation while cytoplasmic p21 may be associated with anti-apoptotic and oncogenic functions. REVIEW

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“…Also the other mechanism may be involved in the repression by HBx. (30) HBx may modulate both transcriptional activation and repression because some transcription factors and /or transcription cofactors are involved in positive and negative ways to transcription in different promoters in different cells.…”

Section: −10mentioning

confidence: 99%

Molecular functions and biological roles of hepatitis B virus x protein

Tang¹,

Oishi²,

Kaneko³

et al. 2006

Cancer Science

266

244

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Chronic infection of hepatitis B virus (HBV) isH epatitis B virus (HBV) infection is a worldwide health problem and is one of the major causes of hepatocellular carcinoma (HCC) in the world. However, new incidences of HBV infection have been dramatically reduced by several prevention programs. The crucial role of HBV in hepatocarcinogenesis is beyond doubt, however, the mechanism by which HBV causes transformation of hepatocytes remains uncertain.(1-3) Hepatitis B virus X protein (HBx) has long been suspected to play a positive role in hepatocarcinogenesis because HCC incidence has been reported in animals infected with mammalian hepadnaviruses. Among these hepadnaviruses, open reading frame-X (X-ORF) is conserved in the genomes. However, hepatocarcinogenesis has not been found in avian infected with avian hepadnaviruses where X-ORF is absent. In addition to the putative contribution of HBx, other oncogenic mechanisms of the HBV-related hepatocarcinogenesis have also been proposed, such as the integration-dependent scenario of HBV DNA in host genomes, (4) and the inflammation-dependent scenario.(5) Since no higher incidence of HCC has been reported in HBV-expressing transgenic mice, (6) host immunological responses to HBV infection (but not HBV proliferation by itself ) might be primarily contributing to the HBV-related hepatocarcinogenesis. HBx, a small protein of 154 amino acids, is a multifunctional regulator that modulates a variety of host processes through directly or indirectly interacting with virus and host factors. (2,3) In this short review, we briefly summarize the life cycle of HBV, expression of HBx, and the molecular functions of HBx. We then focus on the recent progress on the biological roles of HBx in HBV replication and cellular transformation. Expression and functions of HBx. HBV is a prototype of Hepadnaviridae, hepatotropic small DNA viruses, of which hosts are among limited species of water birds, squirrels and primates. The HBV genome is a 3.2-kb circular, partially double-stranded DNA molecule with four overlapping ORFs, PC-C, PS-S, P, and X-ORFs (Fig. 1). (7) Once HBV infection of hepatocytes occurs, its genome is converted to covalently closed circular (CCC) DNA, which serves as the template for transcription by the host RNA polymerase II, generating the 3.5-, 2.4-, 2.1-, and 0.7-kb transcripts under control of four HBV promoters (Cp, PS1p, Sp, and Xp), respectively (Fig. 1). Two HBV enhancers (Enh I and Enh II) positively regulate transcription of the HBV promoters in combination with the transcription factors that bind these promoters.(7-9) HBV replicates by reverse transcription of the viral pregenomic 3.5-kb RNA (pgRNA) using the HBV polymerase that catalyzes RNA-dependent DNA synthesis and DNA-dependent DNA synthesis. (7,10) The reverse transcription of hepadnaviruses is unique among DNA viruses, and the primer of the reverse transcription is a tyrosine residue of an N-terminal domain of Pol that is distinct from reverse transcription of retroviruses. (10)

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Transcriptional repression of p21waf1 promoter by hepatitis B virus X protein via a p53-independent pathway

Cited by 51 publications

References 23 publications

Influence of Ursodeoxycholate–Enriched Diet on Liver Tumor Growth in Hbv Transgenic Mice

Influence of Ursodeoxycholate–Enriched Diet on Liver Tumor Growth in Hbv Transgenic Mice

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Molecular functions and biological roles of hepatitis B virus x protein

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