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.
J Virol. 2018 Apr 13;92(9). doi: 10.1128/JVI.00033-18. Print 2018 May 1.
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.
高血浆乳酸与许多恶性肿瘤的预后不良有关，但它在病毒介导的癌症进展中的作用及其潜在的分子机制尚不清楚。爱泼斯坦-巴尔病毒（EBV）是第一种人类致癌病毒，可引起多种癌症，包括 B 细胞淋巴瘤。在这里，我们报告乳酸脱氢酶 A（LDH-A）的表达和乳酸的产生在 EBV 永生化 B 淋巴母细胞中升高，并且低浓度的乳酸（LA；酸性乳酸）触发 EBV 感染的 B 细胞黏附、形态变化和增殖。此外，LA 诱导 EBV 感染的 B 细胞的反应仅发生在病毒潜伏型 III 中，并且与全局病毒 microRNAs 的抑制，特别是 miR-BHRF1 簇，以及基因的高表达显著相关。miR-BHRF1-1 的引入阻止了 LA 诱导的 EBV 感染的 B 细胞的作用。因此，这可能是一种新的机制，可以解释 LA 微环境中 EBV 永生化 B 淋巴母细胞恶性肿瘤的发生机制。肿瘤微环境是复杂的，细胞代谢产生的乳酸有助于酸性微环境，促进癌症的进展。然而，LA 如何在与病毒相关的癌症中发挥作用尚不清楚。因此，我们研究了 EBV（第一个在人类中发现的肿瘤病毒；与许多癌症有关）如何上调 B 淋巴瘤细胞中 LDH-A 的表达和乳酸的产生。升高的 LA 通过抑制病毒 microRNA 转录来诱导 EBV 感染的 B 细胞黏附和生长。因此，我们提供了一种新的认识，即 EBV 如何利用酸性微环境促进癌症的发展。
