Hoppe-Seyler Karin, Honegger Anja, Bossler Felicitas, Sponagel Jasmin, Bulkescher Julia, Lohrey Claudia, Hoppe-Seyler Felix
Molecular Therapy of Virus-Associated Cancers (F065), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Oncotarget. 2017 Nov 15;8(63):106342-106351. doi: 10.18632/oncotarget.22463. eCollection 2017 Dec 5.
Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. Cancer cells typically exhibit metabolic alterations which support their malignant growth. These include an enhanced rate of aerobic glycolysis ('Warburg effect') which in cancer cells is often linked to an increased expression of the rate-limiting glycolytic enzyme Hexokinase 2 (HK2). Intriguingly, recent studies indicate that the HPV oncogenes cause the metabolic reprogramming in HPV-positive cancer cells by directly upregulating HK2 expression. Notably, however, these results were obtained upon ectopic overexpression of E6/E7. Here, we investigated whether HK2 levels are affected by the endogenous E6/E7 amounts present in HPV-positive cancer cell lines. RNA interference analyses reveal that the sustained E6/E7 expression is critical to maintain HK2 expression levels in HeLa cells. Mechanistically, this effect is linked to the E6/E7-dependent upregulation of -stimulatory MYC expression and the E6/E7-induced downregulation of the -inhibitory micro(mi)RNA miR-143-3p. Importantly, however, a stimulatory effect of E6/E7 on HK2 expression was observed only in HeLa among a panel of 8 different HPV-positive cervical and head and neck cancer cell lines. Thus, whereas these results support the notion that E6/E7 can increase HK2 expression, they argue against the concept that the viral oncogenes, at endogenous expression levels, commonly induce the metabolic switch of HPV-positive cancer cells towards aerobic glycolysis by directly or indirectly stimulating HK2 expression.
致癌型人乳头瘤病毒（HPV）是主要的人类致癌物。癌细胞通常表现出支持其恶性生长的代谢改变。这些改变包括有氧糖酵解速率增强（“瓦伯格效应”），在癌细胞中这通常与限速糖酵解酶己糖激酶2（HK2）表达增加有关。有趣的是，最近的研究表明，HPV致癌基因通过直接上调HK2表达导致HPV阳性癌细胞中的代谢重编程。然而，值得注意的是，这些结果是在E6/E7异位过表达后获得的。在这里，我们研究了HK2水平是否受HPV阳性癌细胞系中内源性E6/E7含量的影响。RNA干扰分析表明，持续的E6/E7表达对于维持HeLa细胞中的HK2表达水平至关重要。从机制上讲，这种效应与E6/E7依赖的刺激型MYC表达上调以及E6/E7诱导的抑制型微小（mi）RNA miR-143-3p下调有关。然而，重要的是，在一组8种不同的HPV阳性宫颈癌和头颈癌细胞系中，仅在HeLa细胞中观察到E6/E7对HK2表达的刺激作用。因此，虽然这些结果支持E6/E7可以增加HK2表达的观点，但它们反对病毒致癌基因在内源性表达水平上通常通过直接或间接刺激HK2表达诱导HPV阳性癌细胞向有氧糖酵解代谢转换的概念。
