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Molecular Pathogenesis of Viral Hepatitis and Liver Cancer

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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 March 2021) | Viewed by 37538

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Special Issue Editor

Prof. Jin‐Wook Kim

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Guest Editor

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
Interests: hepatitis B virus; hepatitis C virus; hepatocellular carcionoma; combined HCC–CCC

Special Issue Information

Dear Colleagues,

Viral hepatitis and related liver cancer remains a global health burden, despite the successful development of antiviral treatment and targeted molecular anti-cancer therapy. The unsolved issues include, but are not limited to, the following:

- Viral carcinogenesis
- Cure of chronic hepatitis B
- Mechanisms of hepatocellular carcinoma in patients with complete viral suppression and risk prediction
- Long-term effect of antiviral therapy
- Pathogenesis of combined hepatocellular carcinoma–cholangiocarcinoma
- Cancer immunotherapy

This Special Issue aims to cover the current understanding and cutting-edge research on these rapidly evolving fields in hepatology, and we invite contributions of reviews and/or original papers reporting recent efforts in this field.

Prof. Jin‐Wook Kim
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Hepatitis B virus
Hepatitis C virus
Viral carcinogenesis
Functional cure
Hepatocellular carcinoma in patients with complete viral suppression
Long-term effect of antiviral therapy
Pathogenesis of combined hepatocellular carcinoma–cholangiocarcinoma
Cancer immunotherapy

Published Papers (7 papers)

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Research

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11 pages, 3005 KiB

Open AccessArticle

Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma

by Dong-Jun Park, Pil-Soo Sung, Gil-Won Lee, Sung-Woo Cho, Sung-Min Kim, Byung-Yoon Kang, Won-Hee Hur, Hyun Yang, Soon-Kyu Lee, Sung-Hak Lee, Eun-Sun Jung, Chang-Ho Seo, Joseph Ahn, Ho-Joong Choi, Young-Kyoung You, Jeong-Won Jang, Si-Hyun Bae, Jong-Young Choi and Seung-Kew Yoon

Int. J. Mol. Sci. 2021, 22(9), 4710; https://doi.org/10.3390/ijms22094710 - 29 Apr 2021

Cited by 23 | Viewed by 3688

Abstract

A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68⁺ macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8⁺ T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4⁺ and CD8⁺ T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8⁺ T cells in HCC. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Viral Hepatitis and Liver Cancer)

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13 pages, 1706 KiB

Open AccessArticle

Chronic HCV Infection Is Associated with Overexpression of Human Endogenous Retroviruses that Persists after Drug-Induced Viral Clearance

by Pier-Angelo Tovo, Silvia Garazzino, Valentina Daprà, Carla Alliaudi, Erika Silvestro, Cristina Calvi, Paola Montanari, Ilaria Galliano and Massimiliano Bergallo

Int. J. Mol. Sci. 2020, 21(11), 3980; https://doi.org/10.3390/ijms21113980 - 1 Jun 2020

Cited by 20 | Viewed by 2458

Abstract

Chronic hepatitis C virus (HCV) infection is associated with several hepatic and extrahepatic complications, including cancers and autoimmune disorders, whose frequency is reduced but not abolished after drug-induced viral clearance. The causes of these complications and of their persistence are ill-defined. Human endogenous retroviruses (HERVs) are remnants of ancestral infections and constitute 8% of the human genome. Most HERV elements are inactive, but some are transcribed. HERV overexpression is associated with many cancers and autoimmune diseases with a putative pathogenetic role. Several viral infections trigger HERV activation, but there are no studies on HCV-infected subjects. We assessed, through a PCR real-time amplification assay, the transcription levels of the pol genes of HERV-H, -K, and -W, and of their repressor TRIM28 in white blood cells (WBCs) of vertically infected children, both before and after therapy with direct-acting antivirals (DAAs). The results documented significantly higher expressions of HERV-H-pol and HERV-K-pol, not of HERV-W-pol, in HCV-infected subjects as compared to age-matched controls. HERV RNA levels remained unchanged after DAA-driven viral clearance. No significant variations in transcription levels of TRIM28 were observed in infected subjects. Our findings demonstrate HERV-H-pol and HERV-K-pol overexpression in subjects with chronic HCV infection, without variations after a positive response to DAAs; this might justify their predisposition to cancers and autoimmune disorders that persist after a DAA-induced resolution of viremia. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Viral Hepatitis and Liver Cancer)

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19 pages, 2305 KiB

Open AccessArticle

Suppression of Hepatocyte Nuclear Factor 4 α by Long-term Infection of Hepatitis B Virus Contributes to Tumor Cell Proliferation

by Soree Park, Yea Na Ha, Mehrangiz Dezhbord, Ah Ram Lee, Eun-Sook Park, Yong Kwang Park, Juhee Won, Na Yeon Kim, Soo Yeun Choo, Jae Jin Shin, Chang Hyun Ahn and Kyun-Hwan Kim

Int. J. Mol. Sci. 2020, 21(3), 948; https://doi.org/10.3390/ijms21030948 - 31 Jan 2020

Cited by 7 | Viewed by 3789

Abstract

Hepatitis B virus (HBV) infection is a major factor in the development of various liver diseases such as hepatocellular carcinoma (HCC). Among HBV encoded proteins, HBV X protein (HBx) is known to play a key role in the development of HCC. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear transcription factor which is critical for hepatocyte differentiation. However, the expression level as well as its regulatory mechanism in HBV infection have yet to be clarified. Here, we observed the suppression of HNF4α in cells which stably express HBV whole genome or HBx protein alone, while transient transfection of HBV replicon or HBx plasmid had no effect on the HNF4α level. Importantly, in the stable HBV- or HBx-expressing hepatocytes, the downregulated level of HNF4α was restored by inhibiting the ERK signaling pathway. Our data show that HNF4α was suppressed during long-term HBV infection in cultured HepG2-NTCP cells as well as in a mouse model following hydrodynamic injection of pAAV-HBV or in mice intravenously infected with rAAV-HBV. Importantly, HNF4α downregulation increased cell proliferation, which contributed to the formation and development of tumor in xenograft nude mice. The data presented here provide proof of the effect of HBV infection in manipulating the HNF4α regulatory pathway in HCC development. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Viral Hepatitis and Liver Cancer)

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16 pages, 5586 KiB

Open AccessArticle

PreS1 Mutations Alter the Large HBsAg Antigenicity of a Hepatitis B Virus Strain Isolated in Bangladesh

by Md. Golzar Hossain, Md. Muket Mahmud, K. H. M. Nazmul Hussain Nazir and Keiji Ueda

Int. J. Mol. Sci. 2020, 21(2), 546; https://doi.org/10.3390/ijms21020546 - 15 Jan 2020

Cited by 16 | Viewed by 3914

Abstract

Mutations in the hepatitis B virus (HBV) genome can potentially lead to vaccination failure, diagnostic escape, and disease progression. However, there are no reports on viral gene expression and large hepatitis B surface antigen (HBsAg) antigenicity alterations due to mutations in HBV isolated from a Bangladeshi population. Here, we sequenced the full genome of the HBV isolated from a clinically infected patient in Bangladesh. The open reading frames (ORFs) (P, S, C, and X) of the isolated HBV strain were successfully amplified and cloned into a mammalian expression vector. The HBV isolate was identified as genotype C (sub-genotype C2), serotype adr, and evolutionarily related to strains isolated in Indonesia, Malaysia, and China. Clinically significant mutations, such as preS1 C2964A, reverse transcriptase domain I91L, and small HBsAg N3S, were identified. The viral P, S, C, and X genes were expressed in HEK-293T and HepG2 cells by transient transfection with a native subcellular distribution pattern analyzed by immunofluorescence assay. Western blotting of large HBsAg using preS1 antibody showed no staining, and preS1 ELISA showed a significant reduction in reactivity due to amino acid mutations. This mutated preS1 sequence has been identified in several Asian countries. To our knowledge, this is the first report investigating changes in large HBsAg antigenicity due to preS1 mutations. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Viral Hepatitis and Liver Cancer)

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Review

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16 pages, 1978 KiB

Open AccessReview

Tissue-Resident Lymphocytes: Implications in Immunotherapy for Hepatocellular Carcinoma

by Ji Won Han and Seung Kew Yoon

Int. J. Mol. Sci. 2021, 22(1), 232; https://doi.org/10.3390/ijms22010232 - 28 Dec 2020

Cited by 7 | Viewed by 3265

Abstract

Hepatocellular carcinoma (HCC) is a hard-to-treat cancer. The recent introduction of immune checkpoint inhibitors (ICIs) provided viable options to treat HCC, but the response rate is currently not sufficient. Thus, a better understanding of ICI-responding cells within tumors is needed to improve outcomes of ICI treatment in HCC. Recently, tissue-resident memory T (T_RM) cells were defined as a subset of the memory T cell population; this cell population is actively under investigation to elucidate its role in anti-tumor immunity. In addition, the role of other tissue-resident populations such as tissue resident regulatory T (Treg) cells, mucosal associated invariant T (MAIT) cells, γδ T cells, and invariant natural killer T (iNKT) cells in anti-tumor immunity is also actively being investigated. However, there is no study that summarizes recent studies and discusses future perspectives in terms of tissue resident lymphocytes in HCC. In this review, we summarize key features of tissue-resident lymphocytes and their role in the anti-tumor immunity. Additionally, we review recent studies regarding the characteristics of tissue-resident lymphocytes in HCC and their role in ICI treatment and other immunotherapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Viral Hepatitis and Liver Cancer)

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20 pages, 324 KiB

Open AccessReview

Recent Updates of Transarterial Chemoembolilzation in Hepatocellular Carcinoma

by Young Chang, Soung Won Jeong, Jae Young Jang and Yong Jae Kim

Int. J. Mol. Sci. 2020, 21(21), 8165; https://doi.org/10.3390/ijms21218165 - 31 Oct 2020

Cited by 146 | Viewed by 9503

Abstract

Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC). In this review, we summarize recent updates on the use of TACE for HCC. TACE can be performed using two techniques; conventional TACE (cTACE) and drug-eluting beads using TACE (DEB-TACE). The anti-tumor effect of the two has been reported to be similar; however, DEB-TACE carries a higher risk of hepatic artery and biliary injuries and a relatively lower risk of post-procedural pain than cTACE. TACE can be used for early stage HCC if other curative treatments are not feasible or as a neoadjuvant treatment before liver transplantation. TACE can also be considered for selected patients with limited portal vein thrombosis and preserved liver function. When deciding to repeat TACE, the ART (Assessment for Retreatment with TACE) score and ABCR (AFP, BCLC, Child-Pugh, and Response) score can guide the decision process, and TACE refractoriness needs to be considered. Studies on the combination therapy of TACE with other treatment modalities, such as local ablation, radiation therapy, or systemic therapy, have been actively conducted and are still ongoing. Recently, new prognostic models, including analysis of the neutrophil-lymphocyte ratio, radiomics, and deep learning, have been developed to help predict survival after TACE. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Viral Hepatitis and Liver Cancer)

19 pages, 1636 KiB

Open AccessReview

Novel Biomarkers of Hepatitis B and Hepatocellular Carcinoma: Clinical Significance of HBcrAg and M2BPGi

by Ian Baudi, Takako Inoue and Yasuhito Tanaka

Int. J. Mol. Sci. 2020, 21(3), 949; https://doi.org/10.3390/ijms21030949 - 31 Jan 2020

Cited by 31 | Viewed by 10042

Abstract

The hepatitis B virus (HBV) cannot be removed completely from infected hepatocytes, owing to the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), predicting HCC development in high-risk patients with high viral replicative activity or advanced fibrosis is important. Novel serological biomarkers reflect intrahepatic viral replicative activity or the progression of liver fibrosis, indicating non-invasive alternatives to liver biopsy: (1) Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients, a decrease in HBcrAg is associated with favorable outcomes. HBcrAg can predict HCC occurrence or recurrence. (2) Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. An increase in M2BPGi in CHB patients is related to the progression of liver fibrosis and high potential (risk) of HCC development. Here, we describe the clinical applications of HBcrAg and M2BPGi in CHB patients. Additionally, because new potential therapeutic agents that eliminate intrahepatic cccDNA are being developed, monitoring of HBcrAg or M2BPGi might be suitable for evaluating therapeutic effects and the clinical outcomes. In conclusion, these would be appropriate surrogate markers for predicting disease progression. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Viral Hepatitis and Liver Cancer)

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