Abstract Topic: 20. Lymphoma Biology & Translational Research
Background: Hepatitis B virus (HBV) is an oncogenic virus known to contribute to hepatocellular carcinoma (HCC) development through a variety of mechanisms such as activation of the innate immune response triggering inflammatory signaling in liver cells; integration of HBV-DNA into the host genome, leading to genetic modifications; the ER stress induced by accumulation of viral proteins and the modulation of signaling pathways involved in cell cycle and proliferation by viral proteins. The scientific evidence is mainly focused on its implication in hepatic cancer, but several clinical and epidemiological studies support a role for HBV in extrahepatic diseases, such as B-cell non-Hodgkin lymphoma (B-NHL) occurrence. However, the mechanistic association between the HBV infection, the onset and progression of lymphoma remains unclear at the moment.
Aims: The aim of our work is to investigate the potential role of HBV in lymphomagenesis by activating the endoplasmic reticulum (ER) stress and modulate the Unfolded Protein Response (UPR) signaling pathways.
Methods: IM-9 cells (ATCC) were exposed to infectious HBV particles in order to investigate the ability of B lymphocytes to sustain productive HBV replication. HBV infection was assessed by qPCR, western blotting and ELISA. Regulation of UPR cellular signaling pathways IRE1α (Inositol-Requiring Enzyme 1), the transcription factor ATF6α and protein kinase PERK were evaluated by western blotting and RT-PCR.
Results: Detection of HBV viral proteins, the accumulation of subviral and infectious particles in the B lymphocyte cell line suggest an active HBV replication, results confirmed by the binding assays of specific HBV entry inhibitors (myrcludex). IRE1α and ATF6α protein expression levels are overexpressed in HBV-infected B cells, while the expression of PERK proteins was not changed. A key regulator of tumorigenesis, the active form of XBP1 (spliced XBP1) mRNA generated from unspliced form by IRE1 during UPR was also increased in HBV infected cells.
Summary/Conclusion
The results obtained reveal new information regarding the etiology of HBV infection and potential mechanisms involved in the malignant transformation of B lymphocytes, information that may facilitate identification of new potential B-NHL triggers.
Keywords: Hepatitis B virus, Lymphomagenesis, B cell lymphoma, B lymphocyte