Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR.
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
J Virol. 2020 Mar 31;94(8). doi: 10.1128/JVI.00090-20.
Human papillomavirus (HPV) type 58 is the third most commonly detected HPV type in cervical cancer among Eastern Asians. Our previous international epidemiological studies revealed that HPV58 carrying an E7 natural variant, T20I/G63S (designated V1), was associated with a higher risk of cervical cancer. We recently showed that V1 possesses a greater ability to immortalize and transform primary cells, as well as degrading pRB more effectively, than the prototype and other common variants. In this study, we performed a series of phenotypic and molecular assays using physiologically relevant and models to compare the oncogenicity of V1 with that of the prototype and other common natural variants. Through activation of the AKT and K-Ras/extracellular signal-regulated kinase (ERK) signaling pathways, V1 consistently showed greater oncogenicity than the prototype and other variants, as demonstrated by increased cell proliferation, migration, and invasion, as well as induction of larger tumors in athymic nude mice. This study complements our previous epidemiological and molecular observations pinpointing the higher oncogenicity of V1 than that of the prototype and all other common variants. Since V1 is more commonly found in eastern Asia, our report provides insight into the design of HPV screening assays and selection of components for HPV vaccines in this region. Epidemiological studies have revealed that a wild-type variant of HPV58 carrying an E7 variation, T20I/G63S (V1), is associated with a higher risk of cervical cancer. We previously reported that this increased oncogenicity could be the result of the virus's greater ability to degrade pRB, thereby leading to an increased ability to grow in an anchorage-independent manner. In addition to this, this report further showed that this HPV variant induced activation of the AKT and K-Ras/ERK signaling pathways, thereby explaining its genuine oncogenicity in promoting cell proliferation, migration, invasion, and formation of tumors, all to a greater extent than the prototype HPV58 and other common variants.
人乳头瘤病毒（HPV）类型 58 是东亚宫颈癌中第三常见的 HPV 类型。我们之前的国际流行病学研究表明，携带 E7 天然变异体 T20I/G63S（指定为 V1）的 HPV58 与宫颈癌风险增加相关。我们最近表明，V1 具有更大的能力使原代细胞永生化和转化，以及更有效地降解 pRB，而原型和其他常见变体则不然。在这项研究中，我们使用生理相关的模型进行了一系列表型和分子测定，以比较 V1 与原型和其他常见天然变体的致癌性。通过激活 AKT 和 K-Ras/细胞外信号调节激酶（ERK）信号通路，V1 始终表现出比原型和其他变体更高的致癌性，表现为细胞增殖、迁移和侵袭增加，以及在免疫缺陷裸鼠中诱导更大的肿瘤。这项研究补充了我们之前的流行病学和分子观察结果，指出 V1 的致癌性高于原型和所有其他常见变体。由于 V1 在东亚更为常见，我们的报告为该地区 HPV 筛查检测的设计和 HPV 疫苗成分的选择提供了参考。流行病学研究表明，携带 E7 变异 T20I/G63S（V1）的 HPV58 野生型变体与宫颈癌风险增加相关。我们之前报道过，这种致癌性的增加可能是由于病毒降解 pRB 的能力增强，从而导致其在无锚定依赖性生长方面的能力增强。除此之外，本报告进一步表明，这种 HPV 变体诱导 AKT 和 K-Ras/ERK 信号通路的激活，从而解释了其在促进细胞增殖、迁移、侵袭和肿瘤形成方面的真正致癌性，所有这些都比原型 HPV58 和其他常见变体更为显著。
