School of Biomedical Sciences and Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.
Rev Med Virol. 2015 Mar;25 Suppl 1:24-53. doi: 10.1002/rmv.1823.
Human papillomaviruses (HPVs) are small double-stranded circular DNA viruses with 8 kb genomes. So far, more than 150 HPVs have been identified, and 12 types of HPVs have been conclusively linked to cancer by the International Agency for Research on Cancer/World Health Organization. Expression of HPV E5, E6 and E7 oncoproteins can alter multiple signaling pathways to cause cancer. In this review, the signaling pathways activated by these oncoproteins are summarized, and targeted therapy against key signaling molecules is described. E6 can inactivate tumor protein 53 and PDZ (post synaptic density protein-drosophila disk large tumor suppressor-zonula occludens-1 proteins) while stimulating phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), Wnt and Notch pathways. E7 can inhibit retinoblastoma protein and stimulate the PI3K/Akt pathway. Both E6 and E7 can deregulate cellular microRNA expression, which can alter cellular signaling pathways. E5 can sensitize epidermal growth factor receptor to epidermal growth factor to increase activation of PI3K/Akt and mitogen-activated protein kinase pathways. E5 can also inhibit the extrinsic apoptotic pathway. These altered signaling pathways could be critical for the initiation and maintenance of HPV-associated cancers. Therefore, targeted therapy against the key signaling molecules has therapeutic implications. Among these, the possibilities of targeting PI3K/Akt, mammalian target of rapamycin, epidermal growth factor receptor and vascular endothelial growth factor have been extensively studied in many cancers. Some inhibitors have been studied in cervical cancer in both animal models and clinical trials. Although the results are promising, further investigation is warranted.
人乳头瘤病毒（HPV）是一种小的双链环状 DNA 病毒，基因组大小为 8kb。迄今为止，已经鉴定出超过 150 种 HPV，国际癌症研究机构/世界卫生组织已经明确将 12 种 HPV 与癌症联系起来。HPV E5、E6 和 E7 癌蛋白的表达可以改变多种信号通路导致癌症。在这篇综述中，总结了这些癌蛋白激活的信号通路，并描述了针对关键信号分子的靶向治疗。E6 可以使肿瘤蛋白 53 和 PDZ（突触后密度蛋白-果蝇盘状大肿瘤抑制因子-连接蛋白-1 蛋白）失活，同时刺激磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（Akt）、Wnt 和 Notch 通路。E7 可以抑制视网膜母细胞瘤蛋白并刺激 PI3K/Akt 通路。E6 和 E7 都可以使细胞微 RNA 表达失调，从而改变细胞信号通路。E5 可以使表皮生长因子受体对表皮生长因子敏感，从而增加 PI3K/Akt 和丝裂原活化蛋白激酶通路的激活。E5 还可以抑制细胞外凋亡途径。这些改变的信号通路可能对 HPV 相关癌症的发生和维持至关重要。因此，针对关键信号分子的靶向治疗具有治疗意义。其中，针对 PI3K/Akt、哺乳动物雷帕霉素靶蛋白、表皮生长因子受体和血管内皮生长因子的靶向治疗在许多癌症中已经进行了广泛研究。一些抑制剂已在动物模型和临床试验中进行了宫颈癌研究。尽管结果很有希望，但仍需要进一步研究。
