Shrestha Prabha, Davis David A, Veeranna Ravindra P, Carey Robert F, Viollet Coralie, Yarchoan Robert
HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
PLoS Pathog. 2017 Sep 18;13(9):e1006628. doi: 10.1371/journal.ppat.1006628. eCollection 2017 Sep.
Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma with poor prognosis caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Previous studies have revealed that HIF-1α, which mediates much of the cellular response to hypoxia, plays an important role in life cycle of KSHV. KSHV infection promotes HIF-1α activity, and several KSHV genes are in turn activated by HIF-1α. In this study, we investigated the effects of knocking down HIF-1α in PELs. We observed that HIF-1α knockdown in each of two PEL lines leads to a reduction in both aerobic and anaerobic glycolysis as well as lipid biogenesis, indicating that HIF-1α is necessary for maintaining a metabolic state optimal for growth of PEL. We also found that HIF-1α suppression leads to a substantial reduction in activation of lytic KSHV genes, not only in hypoxia but also in normoxia. Moreover, HIF-1α knockdown led to a decrease in the expression of various KSHV latent genes, including LANA, vCyclin, kaposin, and miRNAs, under both normoxic and hypoxic conditions. These observations provide evidence that HIF-1α plays an important role in PEL even in normoxia. Consistent with these findings, we observed a significant inhibition of growth of PEL in normoxia upon HIF-1α suppression achieved by either HIF-1α knockdown or treatment with PX-478, a small molecule inhibitor of HIF-1α. These results offer further evidence that HIF-1α plays a critical role in the pathogenesis of PEL, and that inhibition of HIF-1α can be a potential therapeutic strategy in this disease.
原发性渗出性淋巴瘤（PEL）是一种由卡波西肉瘤相关疱疹病毒（KSHV）引起的侵袭性B细胞淋巴瘤，预后较差。先前的研究表明，介导细胞对缺氧的大部分反应的HIF-1α在KSHV的生命周期中起重要作用。KSHV感染促进HIF-1α活性，反过来，几个KSHV基因被HIF-1α激活。在本研究中，我们研究了在PEL中敲低HIF-1α的影响。我们观察到，在两个PEL细胞系中敲低HIF-1α均导致有氧和无氧糖酵解以及脂质生物合成减少，表明HIF-1α是维持PEL生长最佳代谢状态所必需的。我们还发现，抑制HIF-1α不仅在缺氧条件下，而且在常氧条件下均导致裂解性KSHV基因的激活大幅减少。此外，在常氧和缺氧条件下，敲低HIF-1α均导致包括LANA、vCyclin、卡波西蛋白和miRNA在内的各种KSHV潜伏基因的表达降低。这些观察结果提供了证据，表明即使在常氧条件下，HIF-1α在PEL中也起重要作用。与这些发现一致，我们观察到通过敲低HIF-1α或用HIF-1α小分子抑制剂PX-478处理在常氧条件下显著抑制了PEL的生长。这些结果进一步证明HIF-1α在PEL的发病机制中起关键作用，并且抑制HIF-1α可能是这种疾病的一种潜在治疗策略。
