Lactic Acid Downregulates Viral MicroRNA To Promote Epstein-Barr Virus-Immortalized B Lymphoblastic Cell Adhesion and Growth

Abstract

High plasma lactate is associated with poor prognosis of many malignancies, but its role in virally mediated cancer progression and underlying molecular mechanisms are unclear. Epstein-Barr virus (EBV), the first human oncogenic virus, causes several cancers, including B-cell lymphoma. Here, we report that lactate dehydrogenase A (LDH-A) expression and lactate production are elevated in EBV-immortalized B lymphoblastic cells, and lactic acid (LA; acidic lactate) at low concentration triggers EBV-infected B-cell adhesion, morphological changes, and proliferation and Moreover, LA-induced responses of EBV-infected B cells uniquely occurs in viral latency type III, and it is dramatically associated with the inhibition of global viral microRNAs, particularly the miR-BHRF1 cluster, and the high expression of ,, and genes. The introduction of miR-BHRF1-1 blocks the LA-induced effects of EBV-infected B cells. Thus, this may be a novel mechanism to explain EBV-immortalized B lymphoblastic cell malignancy in an LA microenvironment. The tumor microenvironment is complicated, and lactate, which is created by cell metabolism, contributes to an acidic microenvironment that facilitates cancer progression. However, how LA operates in virus-associated cancers is unclear. Thus, we studied how EBV (the first tumor virus identified in humans; it is associated with many cancers) upregulates the expression of LDH-A and lactate production in B lymphoma cells. Elevated LA induces adhesion and the growth of EBV-infected B cells by inhibiting viral microRNA transcription. Thus, we offer a novel understanding of how EBV utilizes an acidic microenvironment to promote cancer development.

STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus

“…KSHV and EBV-negative (BJAB and DG75 from American Type Culture Collection [ATCC], Manassas, VA), KSHV-positive (BC3 and BCBL1 from ATCC) B-lymphoma cells, EBV-positive cells (B95.8 from ATCC and EBV-transformed primary B cell lines LCL in vitro generated in the lab[41]), iSLK (1mg/ml puromycin, 250ug/ml G418, a gift from Shou-Jiang Gao at University of South California) and iSLK-Bac16 (K-iSLK, 1mg/ml hygromycin, 250ug/ml G418 and 1ug/ml puromycin, a gift from Shou-Jiang Gao at University of South California) and iSLK.219 (400 μg/mL hygromycin, 250 μg/mL G418, and 4 μg/mL puromycin[42]) cells were maintained in DMEM medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin and streptomycin (Gibco-BRL). HUVEC (ATCC), and HEK293 (ATCC) cells, were maintained in DMEM supplemented with 10% FBS.…”

LDHB inhibition induces mitophagy and facilitates the progression of CSFV infection

“…In particular, the metabolic regulation of immune cells during health and disease has garnered increasing attention, as the active reconfiguration of immune cell metabolism enables these cells to maintain specific functions [56,57]. For instance, Mo et al found that lactic acid downregulates viral microRNA and promotes the growth of Epstein-Barr virus in immortalized B lymphocytes [58]. Moreover, we, as well as other groups, have found that CSFV infection can alter glycolysis in plasma and cells.…”

Lactate dehydrogenase, an independent risk factor of severe COVID-19 patients: a retrospective and observational study

“…Previous studies also had noted the importance of LDH as an indicator of lung diseases. In a study on Epstein-Barr virus (EBV), researchers found that EBV infected B cells had more LDH transcripts than the uninfected B cells [ 12 ]. In addition, the serum levels of LDH increased in pneumocystis pneumonia (PcP) patients, probably was due to lung injury [ 13 , 14 ].…”