Abstract
Cytotoxic chemotherapy drugs, including doxorubicin, can directly promote hepatitis B virus (HBV) replication, but the mechanism has not been fully clarified. This study investigated the potential mechanism underlying the cytotoxic chemotherapy‐mediated direct promotion of HBV replication. We found that HBV replication and regulatory factor X box 1 gene (RFX1) expression were simultaneously promoted by doxorubicin treatment. The amount of RFX1 bound to the HBV enhancer I was significantly increased under doxorubicin treatment. Furthermore, the activity of doxorubicin in promoting HBV replication was significantly attenuated when the expression of endogenous RFX1 was knocked down, and the EP element of HBV enhancer I, an element that mediated the binding of RFX1 and HBV enhancer I, was mutated. In addition, two different sequences of the conserved EP element were found among HBV genotypes A‐D, and doxorubicin could promote the replication of HBV harboring either of the conserved EP elements. Here, a novel pathway in which doxorubicin promoted HBV replication via RFX1 was identified, and it might participate in doxorubicin‐induced HBV reactivation. These findings would be helpful in preventing HBV reactivation during anticancer chemotherapy.
Highlights
Cancer is the leading cause of human death globally, and nearly one of every six deaths is due to cancer.Human malignancies are responsible for 8.8 million deaths in 2015, and the number of new cases is predicted to rise by approximately 70% over the two decades [1]
The measurement of 3.5 kb hepatitis B virus (HBV) RNA reflects the expressions of the pre-C mRNA and pregenomic RNA (pgRNA), which are regulated by the core promoter/basic core promoter
The results revealed that the levels of 3.5 kb HBV RNA and the total HBV RNA in HepG2.2.15 cells both significantly increased at 1 and 2 days following doxorubicin or epirubicin treatment (Fig. 1B and C)
Summary
Cancer is the leading cause of human death globally, and nearly one of every six deaths is due to cancer.Human malignancies are responsible for 8.8 million deaths in 2015, and the number of new cases is predicted to rise by approximately 70% over the two decades [1]. Cancer is the leading cause of human death globally, and nearly one of every six deaths is due to cancer. Hepatitis B virus (HBV) reactivation has been confirmed to frequently occur in hepatitis B surface antigen (HBsAg)- positive HBV-infected individuals who receive cancer chemotherapy [2,3,4,5,6,7,8,9]. With increasing life expectancy and the expected global increase in new cancer cases, chemotherapy-induced HBV reactivation is likely to become a more serious public health problem [13]. Impaired liver function due to HBV reactivation may lead to a delay or the interruption of the chemotherapy regimen, which is likely to increase the risk of morbidity and mortality associated with the underlying malignancy [14]
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