McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
Cancer Res. 2012 Aug 15;72(16):4008-16. doi: 10.1158/0008-5472.CAN-11-3085. Epub 2012 Jun 13.
High-risk human papillomaviruses (HPV), such as HPV-16, are etiologic agents of a variety of anogenital and oral malignancies, including nearly all cases of cervical cancer. Cervical cancers arising in transgenic mice that express HPV-16 E7 in an inducible manner require the continuous expression of E7 for their maintenance. However, in HPV-associated cancers in vivo, E6 and E7 invariably are coexpressed. In this study, we investigated whether cervical cancers rely on the continuous expression of E7 in the context of constitutively expressed E6. We placed the inducible HPV-16 E7 transgene onto a background in which HPV-16 E6 was constitutively expressed. In transgenic mice with high-grade cervical dysplastic lesions and cervical cancer, repressing the expression of E7 led to the regression of all cancers and the vast majority of high-grade dysplastic lesions. In addition, cervical cancers were occasionally observed in transgenic mice in which E7 was repressed and then reexpressed. Our findings indicate that even in the presence of constitutively expressed E6, the continuous expression of E7 is required for the maintenance of cervical cancers and most precancerous lesions. These data have important implications for the potential clinical use of drugs designed to inhibit the expression and/or function of E7 to treat HPV-associated cancers.
高危型人乳头瘤病毒（HPV），如 HPV-16，是多种肛门生殖器和口腔恶性肿瘤的病因，包括几乎所有宫颈癌病例。在可诱导表达 HPV-16 E7 的转基因小鼠中发生的宫颈癌需要持续表达 E7 才能维持。然而，在体内 HPV 相关癌症中，E6 和 E7 总是共同表达的。在这项研究中，我们研究了在持续表达 E6 的情况下，宫颈癌是否依赖于 E7 的持续表达。我们将可诱导的 HPV-16 E7 转基因置于 HPV-16 E6 持续表达的背景下。在具有高级别宫颈发育不良病变和宫颈癌的转基因小鼠中，抑制 E7 的表达导致所有癌症和绝大多数高级别发育不良病变的消退。此外，在 E7 被抑制然后重新表达的转基因小鼠中偶尔观察到宫颈癌。我们的研究结果表明，即使存在持续表达的 E6，E7 的持续表达也是维持宫颈癌和大多数癌前病变所必需的。这些数据对于潜在的临床应用旨在抑制 E7 表达和/或功能以治疗 HPV 相关癌症的药物具有重要意义。
