br Autophagy and HBV induced HCC Researchers have
Autophagy and HBV-induced HCC Researchers have demonstrated downregulation of autophagy in HBV transgenic liver tumors of mouse models and in human HBV-induced HCC specimens. Kotsafti and his colleagues declared that the expression level of BECN1 mRNA in HCC specimens was considerably lower than in chronic hepatitis tissues . Lan et al. observed that BECN1 and Atg5 expression levels were decreased and were accompanied by p62 accumulation in HBV-induced HCC . A previous report suggested that malignant transformation risk was raised, and HBV-induced liver cell neoplasia progression was stimulated in BECN1-null mice . These findings indicate the negative correlation of autophagy level with HBV-induced HCC tumorigenesis. Although the definite mechanisms of why autophagy is downregulated in HBV-induced HCC remain unclear, some researchers claimed that autophagy may be a target in HCC treatment. Researchers also suggested that autophagy can increase antitumor immune response [, , , , ], induce cell death [, , ], and lead to oncogenic microRNA degradation [77,86,87] (Fig. 1). These reactions may be antitumor effects caused by HBV-induced autophagy.
Implications of autophagy-related therapeutic strategies in HBV-related diseases Autophagy is considered to have a close relation with HBV infection and its related diseases, such as HCC. Several potential therapeutic strategies targeting HBV-induced autophagy have been reported recently. Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, opposed HBV-induced incomplete autophagy via enhancing lysosomal acidification, which was unfavorable for HBV replication . A new compound named NTI-007 has been designed and synthesized to target HBx-BECN1 pathway. NTI-007 significantly inhibits HBsAg and HBeAg in HepG2.2.15 Anacardic acid and may be a novel anti-HBV drug . Meanwhile, Chloroquine (CQ) and hydroxychloroquine (HCQ), classic autophagy inhibitors, are considered as a sensitizer in HCC treatments and is being actively assessed in the clinic . Luteolin, an abundant flavonoid, present in many plants, can also act as an autophagy regulator in HCC . Apart from the small molecule agents, recently, a preclinical evaluation in mouse model suggested that autophagosome-based HBV vaccine could suppress the HBV replication effectively and break the HBV tolerance . A histone acetyltransferase (HAT) called P300/CBP-associated factor (PCAF), was newly found to inhibit HCC growth via regulating cell autophagy in vivo and vitro . Moreover, thyroid hormone T3 is also confirmed to be a novel HCC therapeutic option for its function in selective autophagy .Thus, these autophagy-related drugs provide new therapeutic strategies for better treatments of diseases caused by HBV.
Conclusion and perspective
Introduction An estimated 290 million people worldwide have been infected with the hepatitis B virus (HBV) in 2016 (Polaris Observatory, 2018). Although the prevalence has declined in high-endemicity regions, it still remains over eight percent in Western sub-Saharan Africa and over five percent in Africa and East-Asia (Ott et al., 2012; WHO, 2017a). High-income countries in Western Europe and North America share a very low prevalence of HBV at less than two percent (Ott et al., 2012, Polaris Observatory, 2018; WHO, 2017a). Prior to contact with HBV, immunization is the most effective and safest route to prevent infection; the vaccine is eligible for newborns and adults alike but it is ineffective if the disease is already established (Goyal and Murray, 2014; WHO, 2017a). Particularly in highly endemic populations, mother-to-child transmission is very common, as is infection in young children under five years of age (Goyal and Murray, 2014, Ott et al., 2012; WHO, 2017a). In contrast to a horizontally transmitted infection in older age, this group has the highest risk of becoming chronically infected, with one third developing cirrhosis and liver cancer in adulthood (Goyal and Murray, 2014, Kew, 2010; WHO, 2017a).