OncomiR mdv1-miR-M7-5p promotes avian lymphomatosis by modulating the BCL2/Bax mitochondrial apoptosis signaling pathway.

Marek's disease virus (MDV) is an oncogenic alphaherpesvirus that infects poultry and causes fatal lymphomas in infected chickens. Notably, the mdv1-miR-M7-5p, a pivotal oncomiR encoded by MDV, is closely associated with viral replication and latency. Here, mdv1-miR-M7-5p was transfected into the chicken lymphoma cell line MSB1, which resulted in the inhibition of lymphoma cell apoptosis and an increase in lymphoma cell proliferation and migration. Additionally, the expression of the tumor suppressor genes p53 and ARRDC3 were significantly downregulated, while the MDV latency-associated genes such as ICP4 and ICP27 were significantly upregulated. The BCL2/Bax ratio was increased while the expression of genes involved in the apoptotic signaling pathway were decreased. Furthermore, our mitochondrial function experiments in MSB1 cells demonstrated that mdv1-miR-M7-5p enhanced mitochondrial ATP release and altered the mitochondrial membrane potential, thereby affecting mitochondrial function and inhibiting lymphoma cell apoptosis. Dual-luciferase assays revealed that mdv1-miR-M7-5p binds to caspase-6. For the in vivo study, a cholesterol-modified inhibitor of mdv1-miR-M7-5p was administered to chickens. Inhibition of mdv1-miR-M7-5p resulted in a lower mortality rate than that in the control groups. Furthermore, the expression levels of the cytokines interferon-gamma (IFN-γ), interleukin (IL)-4, and IL-17 in the plasma of MDV-infected chickens were significantly increased. A marked increase was observed in apoptosis in the spleen tissues, and the expression of apoptosis-related genes including caspase-3 and tumor suppressor gene PTEN in immune organs, including the spleen, bursa of Fabricius, and thymus, were markedly upregulated. In summary, the oncogenic miRNA mdv1-miR-M7-5p promotes MDV latency and may facilitate lymphoma formation by mediating the BCL2/CytC signaling pathway. This mediation enhances mitochondrial function and inhibits lymphoma cell apoptosis, thereby contributing to lymphoma development.