Role of hepatitis B virus in development of hepatocellular carcinoma: Focus on covalently closed circular DNA

doi:10.4254/wjh.v14.i5.866

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World Journal of Hepatology

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World J Hepatol. May 27, 2022; 14(5): 866-884
Published online May 27, 2022. doi: 10.4254/wjh.v14.i5.866

Role of hepatitis B virus in development of hepatocellular carcinoma: Focus on covalently closed circular DNA

Caecilia H C Sukowati, Korri Elvanita El-Khobar, Claudio Tiribelli, Elizabeth Sidhartha, Claryssa Bianca

Claryssa Bianca, Elizabeth Sidhartha, Department of Biomedicine, Indonesia International Institute for Life Sciences, Jakarta 13210, Indonesia

Claudio Tiribelli, Caecilia H C Sukowati, Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy

Korri Elvanita El-Khobar, Caecilia H C Sukowati, Eijkman Center for Molecular Biology, National Research and Innovation Agency (BRIN), Jakarta 10340, Indonesia

Author contributions: El-Khobar KE and Sukowati CHC conceived the idea; Bianca C, Sidhartha E, Tiribelli C, El-Khobar KE, and Sukowati CHC wrote the manuscript; all authors read and approved the manuscript.

Supported by

International Cooperation 2021 with Indonesia from the Regione of Friuli Venezia Giulia (Prot. 0015911/P) to the FIF.

Conflict-of-interest statement: All authors declare that there are no conflicts of interest to disclose.

Corresponding author: Caecilia H C Sukowati, BSc, PhD, Senior Researcher, Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, AREA Science Park, campus Basovizza, SS14 km 163.5, Trieste 34149, Italy. caecilia.sukowati@fegato.it

Received: November 30, 2021
Peer-review started: November 30, 2021
First decision: December 26, 2021
Revised: January 31, 2022
Accepted: April 25, 2022
Article in press: April 25, 2022
Published online: May 27, 2022
Processing time: 174 Days and 23.4 Hours

Abstract

Chronic infection with hepatitis B virus (HBV) remains a major global health problem, especially in developing countries. It may lead to prolonged liver damage, fibrosis, cirrhosis, and hepatocellular carcinoma. Persistent chronic HBV infection is related to host immune response and the stability of the covalently closed circular DNA (cccDNA) in human hepatocytes. In addition to being essential for viral transcription and replication, cccDNA is also suspected to play a role in persistent HBV infections or hepatitis relapses since cccDNA is very stable in non-dividing human hepatocytes. Understanding the pathogenicity and oncogenicity of HBV components would be essential in the development of new diagnostic tools and treatment strategies. This review summarizes the role and molecular mechanisms of HBV cccDNA in hepatocyte transformation and hepatocarcinogenesis and current efforts to its detection and targeting.

Keywords: Hepatitis B virus; Covalently closed circular DNA; Hepatocellular carcinoma; Hepatocarcinogenesis

Core Tip: The covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) in human hepatocytes serves as the template for viral replication machinery. HBV cccDNA is also related to host immune response and persistent HBV infection leading to the development of hepatocellular carcinoma. This review summarizes current knowledge on cccDNA in hepatocarcinogenesis and comprehensive efforts to its detection and targeting.