EBV-encoded miRNAs BHRF1-1 and BART2-5p aggravate post- transplant lymphoproliferative disorder via LZTS2-PI3K-AKT...

Post-transplant lymphoproliferative disorder (PTLD) is one of the most serious complications after transplantation. Epstein-Barr virus (EBV) is a key pathogenic driver of PTLD. About 80% of PTLD patients are EBV positive. However, the accuracy of preventing and diagnosing EBV-PTLD by monitoring EBV DNA load is limited. Therefore, new diagnostic molecular markers are urgently needed. EBV-encoded miRNAs can regulate a variety of EBV-associated tumors and are expected to be potential diagnostic markers and therapeutic targets. We found BHRF1-1 and BART2-5p were significantly elevated in EBV-PTLD patients, functionally promoting proliferation and inhibiting apoptosis in EBV-PTLD. Mechanistically, we first found that LZTS2 acts as a tumor suppressor gene in EBV-PTLD, and BHRF1-1 and BART2-5p can simultaneously inhibit LZTS2 and activate PI3K-AKT pathway. This study shows that BHRF1-1 and BART2-5p can simultaneously inhibit the expression of tumor suppressor LZTS2, and activate the PI3K-AKT pathway, leading to the occurrence and development of EBV-PTLD. Therefore, BHRF1-1 and BART2-5p are expected to be potential diagnostic markers and therapeutic targets for EBV-PTLD patients.