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）是一种侵袭性B细胞淋巴瘤，由卡波西氏肉瘤相关疱疹病毒（KSHV）引起的预后不良。先前的研究表明，HIF-1α介导了许多细胞对缺氧的反应，在KSHV的生命周期中起着重要的作用。KSHV感染促进了HIF-1α的活性，而几个KSHV基因又被HIF-1α激活。在这项研究中，我们研究了敲低PEL中HIF-1α的作用。我们观察到，两个PEL品系中的HIF-1α敲低导致有氧和厌氧糖酵解以及脂质生物发生的减少，这表明HIF-1α对于维持最适合PEL生长的代谢状态是必需的。我们还发现，HIF-1α抑制导致溶血性KSHV基因的激活显着降低，不仅在低氧环境中，在常氧环境中也是如此。此外，在常氧和低氧条件下，HIF-1α敲低导致各种KSHV潜在基因（包括LANA，vCyclin，kaposin和miRNA）的表达减少。这些观察结果提供了证据，即HIF-1α甚至在常氧中在PEL中也起着重要的作用。与这些发现一致，我们观察到通过HIF-1α敲低或用HIF-1α的小分子抑制剂PX-478处理达到的HIF-1α抑制后，常氧中PEL的生长受到显着抑制。这些结果提供了进一步的证据，表明HIF-1α在PEL的发病机理中起关键作用，并且抑制HIF-1α可能是该疾病的潜在治疗策略。在常氧和低氧条件下。这些观察结果提供了证据，即HIF-1α甚至在常氧中在PEL中也起着重要的作用。与这些发现一致，我们观察到通过HIF-1α敲低或用HIF-1α的小分子抑制剂PX-478处理达到的HIF-1α抑制后，常氧中PEL的生长受到显着抑制。这些结果提供了进一步的证据，表明HIF-1α在PEL的发病机理中起关键作用，并且抑制HIF-1α可能是该疾病的潜在治疗策略。在常氧和低氧条件下。这些观察结果提供了证据，即HIF-1α甚至在常氧中在PEL中也起着重要的作用。与这些发现一致，我们观察到通过HIF-1α敲低或用HIF-1α的小分子抑制剂PX-478处理达到的HIF-1α抑制后，常氧中PEL的生长受到显着抑制。这些结果提供了进一步的证据，表明HIF-1α在PEL的发病机理中起关键作用，并且抑制HIF-1α可能是该疾病的潜在治疗策略。HIF-1α的小分子抑制剂。这些结果提供了进一步的证据，表明HIF-1α在PEL的发病机理中起关键作用，并且抑制HIF-1α可能是该疾病的潜在治疗策略。HIF-1α的小分子抑制剂。这些结果提供了进一步的证据，表明HIF-1α在PEL的发病机理中起关键作用，并且抑制HIF-1α可能是该疾病的潜在治疗策略。