Oncotarget: HBx is an important therapeutic target in hepatocellular carcinoma


Oncotarget published "Hepatitis B x antigen (HBx) is an important therapeutic target in the pathogenesis of hepatocellular carcinoma" which reported that Hepatitis B virus is a human pathogen that has infected an estimated two billion people worldwide.

Despite the availability of highly efficacious vaccines, universal screening of the blood supply for virus, and potent direct acting anti-viral drugs, there are more than 250 million carriers of HBV who are at risk for the sequential development of hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. More than 800,000 deaths per year are attributed to chronic hepatitis B. Many different therapeutic approaches have been developed to block virus replication, and although effective, none are curative. These treatments have little or no impact upon the portions of integrated HBV DNA, which often encode the virus regulatory protein, HBx.

Dr.Mark A. Feitelson from The Temple University said, "HBV is a major etiologic agent responsible for the development of chronic liver disease (CLD) which may resolve or progress to HCC."

Although there are a variety of treatment options for patients with chronic hepatitis B associated with HCC, prognosis and subsequent survival is poor, in part, because diagnosis is often made late, which limits the potential success of available treatments. Since the carrier state and progression of CLD are major risk factors for the development of HCC, alternative approaches need to be developed to slow the progression of CLD and reduce the risk of HCC and/or more effectively treat HCC upon diagnosis.

Figure 1: Summary of several HBx functions that contribute to the pathogenesis of chronic liver disease and hepatocellular carcinoma.

Figure 1: Summary of several HBx functions that contribute to the pathogenesis of chronic liver disease and hepatocellular carcinoma. Upon infection, HBx stimulates virus gene expression and replication by binding a protein complex containing DDB1 and by inactivating the restriction factor SMC5/6 (blue arrows). Hepatocytes replicating virus may trigger immune responses that result in the generation of reactive oxygen and nitrogen species, perforins, granzymes and pro-inflammatory cytokines. Successive bouts of chronic liver disease and hepatocellular regeneration results in increased integration of HBV DNA fragments encoding HBx, which over time accumulates intracellularly. Cytoplasmic and nuclear HBx epigenetically alter patterns of host gene expression that partially protects infected hepatocytes from immune mediated destruction, thereby allowing continued virus replication (red print). Constitutive activation of NF-κB by HBx is both hepatoprotective and pro-inflammatory. HBx promotes the development of “stemness” by up-regulating expression of Nanog, Klf-4, Oct-3 and c-myc. HBx contributes to fibrosis by promoting expression of TGFβ, and inactivates tumor suppressors, such as p53, and inhibits the activity of poly (ADP-ribose) polymerase (PARP1), permitting accumulation of mutations. Mitochondrial associated HBx also alters cellular energetics and the cellular redox state (increases oxidative stress) (red print). Each of these activities contribute to molecular changes that reflect in altered cell behavior (green arrows) that are defined as cancer hallmarks, which in combination, contribute to the development of hepatocellular carcinoma (orange arrow). CLD: chronic liver disease; DDB1: DNA damage-binding protein 1; HBV: hepatitis B virus, ORF: open reading frame; NF-κB: nuclear factor kappa B; RNS: reactive nitrogen species; ROS: reactive oxygen species; TFIIH: transcription factor II H; TGFβ: transforming grow factor beta.

HBx contributes to pathogenesis in at least three important ways:

HBx contributes to pathogenesis in at least three important ways:

First - HBx acts epigenetically to promote virus gene expression and replication.

Second - HBx helps to protect infected hepatocytes from immune mediated destruction and promotes both cell survival and growth so that the virus will continue to replicate. Both of these roles promote the development and maintenance of chronic infection and the carrier state.

Third - many of the properties that promote CLD progression overlap with hallmarks of cancer, suggesting that HBx contributes to HCC by epigenetically altering patterns of host gene expression, while immune mediated CLD is the host contribution to tumor development. Accordingly, this perspective piece highlights the role of HBx in virus replication and the pathogenesis of HCC, thereby providing strong rationale for pursuing HBx as a therapeutic target of drug development.

The Feitelson Research Team concluded in their Oncotarget Research Output that importantly, chronic inflammatory diseases are often characterized by alterations in the composition of the gut microbiota, referred to as dysbiosis, which is accompanied by a �leaky gut� in which bacteria and bacterial metabolites contribute to hepatitis via portal vein transit. In fact, feeding HBx transgenic mice short chain fatty acids three months prior to the appearance of dysplasia or HCC inhibited the development of these lesions in about half the mice, suggesting a cause and effect relationship. Given that gut bacteria make both pro- and anti-inflammatory metabolites that help to maintain immunological homeostasis via immuno-regulation, treatment resulting in the resolution of dysbiosis may mitigate CLD and its progression to HCC.

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DOI - https://doi.org/10.18632/oncotarget.28077

Full text - https://www.oncotarget.com/article/28077/text/

Correspondence to - Mark A. Feitelson - [email protected]

Keywords - chronic liver disease, hepatocellular carcinoma, HBx, functional cure, epigenetic

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