A cellular gene up-regulated by hepatitis B virus–encoded X antigen promotes hepatocellular growth and survival

Lian, Zhaorui; Liu, Jie; Pan, Jingbo; Şatıroğlu-Tufan, N. Lale; Zhu, Min; Arbuthnot, Patrick; Kew, Michael C.; Clayton, Marcy; Feitelson, Mark A.

doi:10.1053/jhep.2001.25545

Cited by 45 publications

(47 citation statements)

References 39 publications

(43 reference statements)

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“…As a first step, we used an alternative transcript of ABCC6, called URG7 (31), and showed that the expression level of this splice variant changes in parallel with that of ABCC6 upon the various stimuli (Fig. 5) strongly suggesting that the effect of ERK1/2 is transcriptional.…”

Section: Discussionmentioning

confidence: 99%

“…To find out whether P-ERK1/2 acts at the transcriptional or the post-transcriptional level we made use of the URG7 transcript, a splice variant of ABCC6 ending in the 2nd intron of the gene (31). This short, truncated mRNA is transcribed from the same promoter as the ABCC6 transcript but have a different 3Ј-untranslated region leading to different post-transcriptional regulatory mechanisms (splicing and probably mRNA stability).…”

Section: Erk1/2 Activation Correlates With the Expression Level Of Abmentioning

confidence: 99%

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The ERK1/2-Hepatocyte Nuclear Factor 4α Axis Regulates Human ABCC6 Gene Expression in Hepatocytes

Boussac

Ratajewski

Sachrajda

et al. 2010

Journal of Biological Chemistry

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ABCC6 mutations are responsible for the development of pseudoxanthoma elasticum, a rare recessive disease characterized by calcification of elastic fibers. Although ABCC6 is mainly expressed in the liver the disease has dermatologic, ocular, and cardiovascular symptoms. We investigated the transcriptional regulation of the gene and observed that hepatocyte growth factor (HGF) inhibits its expression in HepG2 cells via the activation of ERK1/2. Similarly, other factors activating the cascade also inhibited ABCC6 expression. We identified the ERK1/2 response element in the proximal promoter by luciferase reporter gene assays. This site overlapped with a region conferring the tissue-specific expression pattern to the gene and with a putative hepatocyte nuclear factor 4␣ (HNF4␣) binding site. We demonstrated that HNF4␣ regulates the expression of ABCC6, acts through the putative binding site, and determines its cell type-specific expression. We also showed that HNF4␣ is inhibited by the activation of the ERK1/2 cascade. In conclusion we describe here the first regulatory pathway of ABCC6 expression showing that the ERK1/2-HNF4␣ axis has an important role in regulation of the gene.

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Section: Discussionmentioning

confidence: 99%

Section: Erk1/2 Activation Correlates With the Expression Level Of Abmentioning

confidence: 99%

The ERK1/2-Hepatocyte Nuclear Factor 4α Axis Regulates Human ABCC6 Gene Expression in Hepatocytes

Boussac

Ratajewski

Sachrajda

et al. 2010

Journal of Biological Chemistry

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“…Besides, the multi-functional X protein can transactivate a variety of viral and cellular promoter/enhancer elements, including up-regulating tumor necrosis factor-␣ gene expression in hepatocytes, which could induce intrahepatic inflammatory processes. 16 High replicative strains could also express more X protein in hepatocytes and cause liver injury indirectly. Mutations in the X protein could increase its transactivating effects and upregulate viral or cellular genes, resulting in hepatocellular growth and liver injury.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the X protein could increase its transactivating effects and upregulate viral or cellular genes, resulting in hepatocellular growth and liver injury. 16,17 "Hot-spots" mutations at nucleotides 1764 A3 T and 1766 G3 A in the core promoter and the precore 28th stop mutation have been described as associated with more severe hepatitis. 18 In our study, all isolates had at least 1 of these mutations.…”

Section: Discussionmentioning

confidence: 99%

Replication efficiency and sequence analysis of full‐length hepatitis B virus isolates from hepatocellular carcinoma tissues

Lin

Yao

et al. 2002

Intl Journal of Cancer

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Prolonged replication of hepatitis B virus (HBV) in liver tissues of hepatitis B patients has been considered as an important risk factor for the development of malignancy. Few studies on full-length HBV sequencing in association with the replication efficiency of isolates from HCC tissues have been reported. To study the structural and functional genomics of HBV isolates from Chinese hepatocellular carcinoma (HCC) patients, full-length HBV genomes were amplified from 6 HBV-marker positive HCC tissues and used to transfect HepG2 cells. Five of 6 isolates showed high replicative efficiency. All isolates were of genotype C and "hotspots" mutations were detected in the B cell and T helper (Th) cell epitopes of the envelope and the core region. In addition, the X region of 2 isolates contained a stop-codon mutation that was predicted to result in a truncated X protein. High replicative HBV immune escape mutants that persist in infected hepatocytes could be 1 of the important factors to initiate pathological processes for the development of HCC in Chinese patients. © 2002 Wiley-Liss, Inc. Key words: hepatitis B virus; hepatocellular carcinoma; replicationHepatitis B virus (HBV) belongs to the Hepadnaviridae family, which is unique in possessing a partially double-stranded DNA genome. This genome consists of 4 open reading frames encoding the envelope antigen (S/Pre-S), the core antigen (C/Pre-C), the viral polymerase (P) and a multifunctional transcriptional transactivator, the X protein. In HBV endemic areas, chronic HBV infection is closely associated with hepatocellular carcinoma as more than 90% of Chinese hepatocellular carcinoma (HCC) patients have been found positive for HBV-markers. 1 Although it is generally accepted that carcinogenesis is a multi-step event, the functional properties of HBV strains involved in the early stage of carcinogenesis have not been fully explored. In a previous study, we compared the nucleotide sequence and replicative efficiency of sequential HBV isolates from a Chinese patient who progressed from HBV asymptomatic carrier to hepatocellular carcinoma and showed that post-HCC HBV isolates possessed enhanced replicative efficiency. 2 High replicative HBV strains might be associated with HCC if they led to increased number of infected hepatocytes, resulting in severe liver injury mediated by host immune responses; to emergence of mutants that would escape from host immune surveillance; 3 or to increased rate of integration of viral DNA. To further investigate the incidence and possible roles of high replicative immune escape mutants derived from HCC tissues, we describe the structural and functional analysis of fulllength HBV genomes from 6 independent Chinese HCC tissues. MATERIAL AND METHODS Liver cancer tissue samplesLiver cancer tissues from serum HBsAg-positive hepatocellular carcinoma patients were collected after resection of the tumor and the diagnoses were confirmed by histopathological examination. Sample collection was in accordance with Chinese State Ethic Regulations. The...

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“…The strong epidemiologic relationship between chronic HBV infection and HCC [2,3], and the important contribution of HBx to HCC [22][23][24][25][26], suggest that the molecular pathways altered by HBx are important for tumor development [26]. Previously, HBx has been shown to alter the expression of genes that promote hepatocellular growth, survival, and tumorigenesis [16][17][18][19][20]. These up-regulated proteins appear to trigger corresponding antibody responses that may accompany the onset of critical transforming events.…”

Section: Discussionmentioning

confidence: 99%

Application of HBx-induced anti-URGs as early warning biomarker of cirrhosis and HCC

Wang

Zhao

Wang

et al. 2012

CBM

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Abstract.Background: Hepatitis B virus (HBV) carriers are at high risk for the development of hepatocellular carcinoma (HCC), but there are no reliable markers that will identify such high-risk patients. HBV up-regulates the expression of selected genes (URGs) in the liver during chronic infection. These aberrantly expressed proteins trigger corresponding antibodies (anti-URGs) that appear prior to the detection of HCC. This study was undertaken to see if the anti-URGs could be used as early warning biomarker of HBV-induced liver cirrhosis and HCC. Methods: A cross sectional study using a total of 625 serum samples from HBV infected and uninfected controls were tested for the anti-URGs using specific ELISAs. Results: The number and specificity of anti-URGs correlated with the severity of liver disease Anti-URGs were predominantly present among patients with HBV-associated HCC (55.2%) and cirrhosis (60.7%), and at a lower frequency among patients with chronic hepatitis (35.8%), and at still lower frequencies in most asymptomatic carriers (12.3%) with normal ALT, among patients with chronic hepatitis C (38.5%) and blood donors (0.9%). These anti-URGs were rarely detected in sera from those with tumors other than HCC, except among HBV infected patients with cholangioicarcinoma and in some patients with drug induced hepatitis. 3 or more anti-URGs could precede the diagnosis of cirrhosis or HCC 11.8 months on average, and HBV hepatitis patients with 3 or more anti-URGs have much higher risk (5/20 vs 0/30) to develop cirrhosis and HCC than those patients with less anti-URGs. As the early warning biomarker, 3 or more anti-URGs were served as the threshold to separate the cirrhosis and HCC from others with a moderate sensitivity (58.3%) and specificity (80.0%), which was better than other biomarkers (AFP, AFP-L3, GPC3 and GP73) and would improve up to 70.3% when combined with another biomarker. Conclusions:The results of this clinical validation study suggest that the anti-URGs might have diagnostic/prognostic utility among patients at high risk for the development of cirrhosis and HCC.

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A cellular gene up-regulated by hepatitis B virus–encoded X antigen promotes hepatocellular growth and survival

Cited by 45 publications

References 39 publications

The ERK1/2-Hepatocyte Nuclear Factor 4α Axis Regulates Human ABCC6 Gene Expression in Hepatocytes

The ERK1/2-Hepatocyte Nuclear Factor 4α Axis Regulates Human ABCC6 Gene Expression in Hepatocytes

Replication efficiency and sequence analysis of full‐length hepatitis B virus isolates from hepatocellular carcinoma tissues

Application of HBx-induced anti-URGs as early warning biomarker of cirrhosis and HCC

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