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Hepatitis B Virus and Carcinogenesis—Pathophysiology, Disease and Treatment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 31808

Special Issue Editor

Department of Internal Medicine, Collage of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
Interests: viral hepatitis; viral carcinogenesis; liver cancer; HBV molecular variants and integration; biomarkers; clinical and translational researches in liver diseases

Special Issue Information

Dear Colleagues,

Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). Despite advances in anti-HBV therapies, there is still no cure for HBV. Current antiviral drugs improve overall patient outcomes through the effective suppression of viral replication, but they do not eradicate HBV, particularly the cccDNA, which often causes viral reactivation as well as liver disease progression after cessation of treatment. HCC still occurs in a subset of patients on therapy, even with maintained HBV remission. HBV can drive liver carcinogenesis through direct oncogenic potential such as HBV integration or viral oncoproteins (HBx and LHBs) from intrahepatic cccDNA, which cannot be targeted by current antiviral therapy. In addition, other direct or indirect viral factors can induce HCC, including HBV genotypes, molecular variants (pre-S deletion, mutations in the HBx/precore regions), and viral antigens (HBsAg, HBcrAg, and HBx).

This Special Issue “Hepatitis B Virus and Carcinogenesis—Pathophysiology, Disease and Treatment” of the International Journal of Molecular Sciences aims at providing an updated overview of basic, translational, and clinical knowledge on the virology, pathophysiology, immunology, and molecular genomics of HBV and HBV-associated HCC as well as on the development of innovative diagnostic and therapeutic approaches, while debating their promises and pitfalls.

Prof. Dr. Jeong-Won Jang
Guest Editor

Manuscript Submission Information

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Keywords

  • direct oncogenic potential of HBV
  • HBV molecular variants
  • liver inflammation and immunology
  • intrahepatic cccDNA
  • HBx/HBs oncoproteins
  • HBV integration
  • genomics of HBV and liver cancer
  • targeting for the cure of HBV
  • biomarkers of HBV
  • Basic-clinical translational research in HBV

Published Papers (8 papers)

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Research

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13 pages, 1803 KiB  
Article
Distinct Patterns of HBV Integration and TERT Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma
by Jeong-Won Jang, Hye-Seon Kim, Jin-Seoub Kim, Soon-Kyu Lee, Ji-Won Han, Pil-Soo Sung, Si-Hyun Bae, Jong-Young Choi, Seung-Kew Yoon, Dong-Jin Han, Tae-Min Kim and Lewis R. Roberts
Int. J. Mol. Sci. 2021, 22(13), 7056; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137056 - 30 Jun 2021
Cited by 10 | Viewed by 2292
Abstract
Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with TERT (telomerase reverse transcriptase) alterations in paired [...] Read more.
Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with TERT (telomerase reverse transcriptase) alterations in paired tumor and non-tumor tissues. Compared to those in non-tumors, tumoral integrations occurred less frequently but with higher read counts and were more preferentially observed in genic regions with significant enrichment of integration into promoters. In HBV-related tumors, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT promoter mutation was observed only in tumors (24.2% (8/33)), but not in non-tumors. Only 3.00% (34/1133) of HBV integration sites were shared between tumors and non-tumors. Within the HBV genome, HBV breakpoints were distributed preferentially in the 3’ end of HBx, with more tumoral integrations detected in the preS/S region. The major genes that were recurrently affected by HBV integration included TERT and MLL4 for tumors and FN1 for non-tumors. Functional enrichment analysis of tumoral genes with integrations showed enrichment of cancer-associated genes. The patterns and functions of HBV integration are distinct between tumors and non-tumors. Tumoral integration is often enriched into both human-virus regions with oncogenic regulatory function. The characteristic genomic features of HBV integration together with TERT alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis. Full article
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19 pages, 5342 KiB  
Article
Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes
by Ah Ram Lee, Ju-Yeon Cho, Jong Chul Kim, Mehrangiz Dezhbord, Soo Yeun Choo, Chang Hyun Ahn, Na Yeon Kim, Jae Jin Shin, Soree Park, Eun-Sook Park, Juhee Won, Dong-Sik Kim, Jeong-Hoon Lee and Kyun-Hwan Kim
Int. J. Mol. Sci. 2021, 22(4), 1606; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041606 - 05 Feb 2021
Cited by 3 | Viewed by 2224
Abstract
Tenofovir disoproxil fumarate (TDF) has been regarded as the most potent drug for treating patients with chronic hepatitis B (CHB). However recently, viral mutations associated with tenofovir have been reported. Here, we found a CHB patient with suboptimal response after more than 4 [...] Read more.
Tenofovir disoproxil fumarate (TDF) has been regarded as the most potent drug for treating patients with chronic hepatitis B (CHB). However recently, viral mutations associated with tenofovir have been reported. Here, we found a CHB patient with suboptimal response after more than 4 years of TDF treatment. Clonal analysis of hepatitis B virus (HBV) isolated from sequential sera of this patient identified the seven previously reported TDF-resistant mutations (CYELMVI). Interestingly, a threonine to alanine mutation at the 301 amino acid position of the reverse-transcriptase (RT) domain, (rtT301A), was commonly accompanied with CYELMVI at a high rate (72.7%). Since the rtT301A mutation has not been reported yet, we investigated the role of this naturally occurring mutation on the viral replication and susceptibility to tenofovir in various liver cells (hepatoma cells as well as primary human hepatocytes). A cell-based phenotypic assay revealed that the rtT301A mutation dramatically impaired the replication ability with meaningful reduction in sensitivity to tenofovir in hepatoma cell lines. However, attenuated viral replication by the rtT301A mutation was significantly restored in primary human hepatocytes (PHHs). Our findings suggest that the replication capability and drug sensitivity of HBV is different between hepatoma cell lines and PHHs. Therefore, our study emphasizes that validation studies should be performed not only in the liver cancer cell lines but also in the PHHs to understand the exact viral fitness under antiviral pressure in patients. Full article
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Review

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17 pages, 651 KiB  
Review
Blood-Based Biomarkers in Hepatitis B Virus-Related Hepatocellular Carcinoma, Including the Viral Genome and Glycosylated Proteins
by Sanae Hayashi, Katsuya Nagaoka and Yasuhito Tanaka
Int. J. Mol. Sci. 2021, 22(20), 11051; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011051 - 13 Oct 2021
Cited by 8 | Viewed by 3603
Abstract
Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) development and is a global public health issue. High performance biomarkers can aid the early detection of HCC development in HBV-infected individuals. In addition, advances in the understanding of [...] Read more.
Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) development and is a global public health issue. High performance biomarkers can aid the early detection of HCC development in HBV-infected individuals. In addition, advances in the understanding of the pathogenesis of HBV infection and in clinical laboratory techniques have enabled the establishment of disease-specific tests, prediction of the progression of liver diseases, including HCC, and auxiliary diagnosis of HCC, using blood-based methods instead of biopsies of liver or HCC tissues. Viral factors such as the HBV genotype, HBV genetic mutations, HBV DNA, and HBV-related antigens, as well as host factors, such as tumor-associated proteins and post-translational modifications, especially glycosylated proteins, can be blood-based, disease-specific biomarkers for HCC development in HBV-infected patients. In this review, we describe the clinical applications of viral biomarkers, including the HBV genome and glycosylated proteins, for patients at a risk of HBV-related HCC, based on their molecular mechanisms. In addition, we introduce promising biomarker candidates for practical use, including colony stimulating factor 1 receptor (CSF1R), extracellular vesicles, and cell-free, circulating tumor DNA. The clinical use of such surrogate markers may lead to a better understanding of the risk of disease progression and early detection of HCC in HBV-infected patients, thereby improving their prognosis. Full article
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26 pages, 3520 KiB  
Review
Molecular Mechanisms and Animal Models of HBV-Related Hepatocellular Carcinoma: With Emphasis on Metastatic Tumor Antigen 1
by Yung-Tsung Li, Hui-Lin Wu and Chun-Jen Liu
Int. J. Mol. Sci. 2021, 22(17), 9380; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179380 - 29 Aug 2021
Cited by 2 | Viewed by 3280
Abstract
Hepatocellular carcinoma (HCC) is an important cause of cancer death worldwide, and hepatitis B virus (HBV) infection is a major etiology, particularly in the Asia-Pacific region. Lack of sensitive biomarkers for early diagnosis of HCC and lack of effective therapeutics for patients with [...] Read more.
Hepatocellular carcinoma (HCC) is an important cause of cancer death worldwide, and hepatitis B virus (HBV) infection is a major etiology, particularly in the Asia-Pacific region. Lack of sensitive biomarkers for early diagnosis of HCC and lack of effective therapeutics for patients with advanced HCC are the main reasons for high HCC mortality; these clinical needs are linked to the molecular heterogeneity of hepatocarcinogenesis. Animal models are the basis of preclinical and translational research in HBV-related HCC (HBV-HCC). Recent advances in methodology have allowed the development of several animal models to address various aspects of chronic liver disease, including HCC, which HBV causes in humans. Currently, multiple HBV-HCC animal models, including conventional, hydrodynamics-transfection-based, viral vector-mediated transgenic, and xenograft mice models, as well as the hepadnavirus-infected tree shrew and woodchuck models, are available. This review provides an overview of molecular mechanisms and animal models of HBV-HCC. Additionally, the metastatic tumor antigen 1 (MTA1), a cancer-promoting molecule, was introduced as an example to address the importance of a suitable animal model for studying HBV-related hepatocarcinogenesis. Full article
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12 pages, 1314 KiB  
Review
Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma
by Hyo-Jung Cho and Jae-Youn Cheong
Int. J. Mol. Sci. 2021, 22(15), 8011; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158011 - 27 Jul 2021
Cited by 16 | Viewed by 4156
Abstract
Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and [...] Read more.
Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC. Full article
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19 pages, 331 KiB  
Review
Risk Factors and Biomarkers for Chronic Hepatitis B Associated Hepatocellular Carcinoma
by Vijay Pandyarajan, Rajalakshmi Govalan and Ju Dong Yang
Int. J. Mol. Sci. 2021, 22(2), 479; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020479 - 06 Jan 2021
Cited by 14 | Viewed by 3213
Abstract
Globally, hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality. This is, in part, due to delayed diagnosis and limited therapeutic options with more advanced stages of the disease. Given the prognostic importance of early [...] Read more.
Globally, hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality. This is, in part, due to delayed diagnosis and limited therapeutic options with more advanced stages of the disease. Given the prognostic importance of early diagnosis, novel methods for early detection are in need. Unlike most other cancer types, tissue is not required to diagnose HCC and is frequently avoided given the inherent risks of liver biopsy, so less invasive methods of obtaining tumor material are currently under investigation. Material shed from tumors into the periphery are being investigated for their potential to both surveil and diagnose patients for HCC. These materials include circulating tumor cells, DNA, RNA, and exosomes, and are collectively termed a “liquid biopsy”. In this review article, we discuss the evolving literature regarding the different risk factors for HCC and the types of emerging novel biomarkers that show promise in the prevention and early diagnosis of HCC within the context of HBV infection. Full article
11 pages, 530 KiB  
Review
Liver-Resident Memory CD8+ T Cells: Possible Roles in Chronic HBV Infection
by Ji Won Han and Eui-Cheol Shin
Int. J. Mol. Sci. 2021, 22(1), 283; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010283 - 30 Dec 2020
Cited by 5 | Viewed by 2528
Abstract
Achieving a functional cure for chronic hepatitis B virus (HBV) infection or complete elimination of HBV covalently closed circular DNA (cccDNA) has been challenging in the treatment of patients with chronic HBV infection. Although novel antivirals are being investigated, improving HBV-specific adaptive immune [...] Read more.
Achieving a functional cure for chronic hepatitis B virus (HBV) infection or complete elimination of HBV covalently closed circular DNA (cccDNA) has been challenging in the treatment of patients with chronic HBV infection. Although novel antivirals are being investigated, improving HBV-specific adaptive immune responses is also important for durable viral clearance. Tissue-resident memory CD8+ T (TRM) cells were recently reported as a T-cell population that resides in peripheral tissues and does not recirculate. TRM cells have been studied in the livers of mice and humans. Liver TRM cells have distinct characteristics compared to T cells in peripheral blood or other tissues, which may be associated with the unique microenvironment of the liver. In this review, we describe the characteristics of liver TRM cells and their implications in chronic HBV infection. We emphasize that liver TRM cells can be an immunotherapeutic target for the treatment of chronic HBV infection. Full article
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12 pages, 599 KiB  
Review
Hepatitis B Virus Cure: Targets and Future Therapies
by Hye Won Lee, Jae Seung Lee and Sang Hoon Ahn
Int. J. Mol. Sci. 2021, 22(1), 213; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010213 - 28 Dec 2020
Cited by 43 | Viewed by 9342
Abstract
Chronic hepatitis B virus (HBV) infection is a major global health problem. It can cause progressive liver fibrosis leading to cirrhosis with end-stage liver disease, and a markedly increased risk of hepatocellular carcinoma. In the last two decades, substantial progress has been made [...] Read more.
Chronic hepatitis B virus (HBV) infection is a major global health problem. It can cause progressive liver fibrosis leading to cirrhosis with end-stage liver disease, and a markedly increased risk of hepatocellular carcinoma. In the last two decades, substantial progress has been made in the treatment of chronic hepatitis, B. However, HBV is often reactivated after stopping nucloes(t)ide analogues because antivirals alone do not directly target covalently closed circular DNA, which is the template for all viral RNAs. Therefore, although currently available antiviral therapies achieve suppression of HBV replication in the majority of patients, hepatitis B surface antigen (HBsAg) loss and seroconversion is rarely achieved despite long-term antiviral treatment (HBsAg loss of less than 10% in 5 years). Various clinical trials of agents that interrupt the HBV life cycle in hepatocytes have been conducted. Potential treatment strategies and new agents are emerging as HBV cure. A combination of current and new anti-HBV agents may increase the rate of HBsAg seroclearance; thus, optimized regimens must be validated. Here, we review the newly investigated therapeutic compounds and the results of preclinical and/or clinical trials. Full article
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