Lactic Acid Downregulates Viral MicroRNA To Promote Epstein-Barr Virus-Immortalized B Lymphoblastic Cell Adhesion and Growth
Authors: Fang Wei
Shujuan Du
Yeqiang Liu
Zhenghong Yuan
Caixia Zhu
Qiliang Cai
Qing Zhu
Qian Yu
Fei Tan
Erle S Robertson
Xiaohui Mo
Yuyan Wang
Ling Ding
Yin Tong
Journal: Journal of Virology (2018)
Discipline: MICROBIOLOGY
Keywords: B lymphoma; EBV; lactic acid; microRNA.
Affiliations: MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China., Central Laboratory, Shanghai Dermatology Hospital, Shanghai, People's Republic of China., ShengYushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, People's Republic of China., Division of Hematology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China., Division of Pathology, Shanghai Dermatology Hospital, Shanghai, People's Republic of China., Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America., MOE& MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China .

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 in vitro and in vivo 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 SMAD3, JUN, and COL1A 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.IMPORTANCE 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. 

Retracted: No

PubPeer comments:
 Figure 1B and 2C. * Red boxes: The  day 5 LCL2 panel in Figure 1B looks unexpectedly similar to the B95.8 Mock panel in Figure 2C, albeit in mirror image. ![file] , 
 Figure 4 and 8. * Green boxes: The LA invasion panel (either LCL1 or B95.8 cells, not indicated) in Figure 4C looks unexpectedly similar to the LCL1 LA+NC invasion panel in Figure 8B. ![file] , 
 2021 correction. https: jvi.asm.org content 95 6 e02292-20 Volume 92, no. 9, e00033-18, 2018, https: doi.org 10.1128 JVI.00033-18. Page 5, Fig. 2C: The B95.8 Mock panel is an inadvertent duplicate of Fig. 1B, LCL2 Day5 panel. Page 7, Fig. 4C, left: The LA panel is an inadvertent duplicate of Fig. 8B, LCL1 LA+NC panel. Correction of these data does not change the conclusions. ,