Quantification of Pregenomic RNA and Covalently Closed Circular DNA in Hepatitis B Virus-Related Hepatocellular Carcinoma

Bai, Fugui; Yano, Yoshihiko; Fukumoto, Takumi; Takebe, Atsushi; Tanaka, Motofumi; Kuramitsu, Kaori; Anggorowati, Nungki; Rinonce, Hanggoro Tri; Widasari, Dewiyani Indah; Saito, Masaya; Hirano, Hirotaka; Hayakumo, Takanobu; Seo, Yasushi; Azuma, Takeshi; Ku, Yonson; Hayashi, Yoshitake

doi:10.1155/2013/849290

Cited by 26 publications

(20 citation statements)

References 29 publications

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“…Precore‐pregenomic RNA (preC‐pgRNA) was detected at comparable level in both tumor tissue and non‐neoplastic liver tissue, similar to a previous study of thirty eight HBV‐HCC patients [Bai et al, ]. Together, these results suggest that active viral transcription occurs in both tissue compartments.…”

Section: Discussionsupporting

confidence: 86%

“…HBsAg did correlate with cccDNA copy number in tumor as well as in non-neoplastic liver tissue, suggesting a significant proportion of HBsAg is derived from cccDNA in both compartments. Precore-pregenomic RNA (preC-pgRNA) was detected at comparable level in both tumor tissue and non-neoplastic liver tissue, similar to a previous study of thirty eight HBV-HCC patients [Bai et al, 2013]. Together, these results suggest that active viral transcription occurs in both tissue compartments.…”

Section: Discussionsupporting

confidence: 85%

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Serum hepatitis B surface antigen correlates with tissue covalently closed circular DNA in patients with hepatitis B‐associated hepatocellular carcinoma

Wang

Luan

Warren

et al. 2015

Journal of Medical Virology

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Quantitation of hepatitis B surface antigen (HBsAg) in hepatitis B-associated hepatocellular carcinoma (HBV-HCC) remains to be clearly defined. This study aims to determine the association of HBsAg quantity with intrahepatic HBV viral load and activity in both tumor and non-neoplastic liver of HBV-HCC patients. Data were obtained from 89 prospectively enrolled patients treated with primary liver resection for HBV-HCC at a single Western institution (2008-2013). Circulating HBsAg was quantitated using ELISA. HBV DNA, covalently closed circular (cccDNA) and precore-pregenomic RNA (preC-pgRNA) in both tumor and non-neoplastic liver were quantitated by real-time PCR from fresh liver resection specimens. Circulating HBsAg was detectable in all 89 patients. HBsAg negatively correlated with age, and positively correlated with pre-operative serum AFP and ALT levels. HBsAg correlated with HBV cccDNA copy number in tumor or non-neoplastic liver tissue. It also correlated with preC-pgRNA copy number in non-neoplastic liver tissue. HBsAg did not correlate with serum HBV DNA, total intrahepatic HBV DNA, viral replicative activity or transcriptional activity. In HBV-HCC patients, HBsAg levels correlated with cccDNA copy number in tumor or non-neoplastic liver tissue, suggesting that a greater pool of cccDNA is associated with a higher rate of HBsAg production.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 85%

Serum hepatitis B surface antigen correlates with tissue covalently closed circular DNA in patients with hepatitis B‐associated hepatocellular carcinoma

Wang

Luan

Warren

et al. 2015

Journal of Medical Virology

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“…25,29 HBV DNA was isolated according to standard genomic DNA isolation methods. 30 Briefly, HBV-infected cells were lysed at 65°C for 4 h in lysis buffer (50 mM Tris-HCl, pH 8.0, 50 mM EDTA, 100 mM NaCl, 1% SDS) supplemented with proteinase K (200 μg/ml). HBV DNA was isolated from the lysed cells using the QIAGEN QIAamp DNA mini kit (Qiagen, Hilden, Germany).…”

Section: Figurementioning

confidence: 99%

TMEM2 inhibits hepatitis B virus infection in HepG2 and HepG2.2.15 cells by activating the JAK–STAT signaling pathway

Zhu

Xie

et al. 2016

Cell Death Dis

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We have previously observed the downregulation of TMEM2 in the liver tissue of patients with chronic hepatitis B virus (HBV) infection and in HepG2.2.15 cells with HBV genomic DNA. In the present study, we investigated the role and mechanism of TMEM2 in HepG2 and HepG2.2.15 during HBV infection HepG2 and HepG2.2.15. HepG2 shTMEM2 cells with stable TMEM2 knockdown and HepG2 TMEM2 and HepG2.2.15 TMEM2 cells with stable TMEM2 overexpression were established using lentivirus vectors. We observed reduced expression of TMEM2 in HBV-infected liver tissues and HepG2.2.15 cells. HBsAg, HBcAg, HBV DNA, and HBV cccDNA levels were significantly increased in HepG2 shTMEM2 cells but decreased in HepG2 TMEM2 and HepG2.2.15 TMEM2 cells compared with naive HepG2 cells. On the basis of the western blotting results, the JAK–STAT signaling pathway was inhibited in HepG2 shTMEM2 cells but activated in HepG2 TMEM2 and HepG2.2.15 TMEM2 cells. In addition, reduced and increased expression of the antiviral proteins MxA and OAS1 was observed in TMEM2-silenced cells (HepG2 shTMEM2 cells) and TMEM2-overexpressing cells (HepG2 TMEM2 and HepG2.2.15 TMEM2 cells), respectively. The expression of Interferon regulatory factor 9 (IRF9) was not affected by TMEM2. However, we found that overexpression and knockdown of TMEM2, respectively, promoted and inhibited importation of IRF9 into nuclei. The luciferase reporter assay showed that IRF9 nuclear translocation affected interferon-stimulated response element activities. In addition, the inhibitory effects of TMEM2 on HBV infection in HepG2 shTMEM2 cells was significantly enhanced by pre-treatment with interferon but significantly inhibited in HepG2.2.15 TMEM2 cells by pre-treatment with JAK1 inhibitor. TMEM2 inhibits HBV infection in HepG2 and HepG2.2.15 by activating the JAK–STAT signaling pathway.

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“…Serum HBV RNA levels have the highest accuracy for distinguishing mild (score < 2) from severe liver histopathology. Besides, pgRNA may be present in HCC cells, evoking viral replication in tumor tissues . The detection of pgRNA and cccDNA in tumors was correlated to the absence of tumorous microvascular invasion and to better patient survival.…”

Section: Pgrna and Liver Disease Progressionmentioning

confidence: 99%

Pregenomic RNA: How to assist the management of chronic hepatitis B?

Wen

Xiao

et al. 2019

Reviews in Medical Virology

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Pregenomic RNA (pgRNA) is an emerging serological marker for chronic hepatitis B virus (HBV) infection. While pgRNA is principally the template for viral proteins and viral DNAs, additional novel functions for the serum pgRNA have recently been described. These results extend for pgRNA a regulatory function in the viral life cycle and potentially a role in pathogenesis. Here, we review the diverse roles of pgRNA in HBV replication and pathogenesis, emphasizing how the unique structure of this RNA is key to its various functions. We focus in particular on the role of HBV pgRNA in guiding antiviral therapy including nucleot(s)ide analog interruption and role as a marker of cure with new curative therapies. We also briefly allude to the emerging niche for new direct-acting or indirect-acting antivirals targeting pgRNA.

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Quantification of Pregenomic RNA and Covalently Closed Circular DNA in Hepatitis B Virus-Related Hepatocellular Carcinoma

Cited by 26 publications

References 29 publications

Serum hepatitis B surface antigen correlates with tissue covalently closed circular DNA in patients with hepatitis B‐associated hepatocellular carcinoma

Serum hepatitis B surface antigen correlates with tissue covalently closed circular DNA in patients with hepatitis B‐associated hepatocellular carcinoma

TMEM2 inhibits hepatitis B virus infection in HepG2 and HepG2.2.15 cells by activating the JAK–STAT signaling pathway

Pregenomic RNA: How to assist the management of chronic hepatitis B?

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