Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Cancer Lett. 2011 Jun 28;305(2):113-22. doi: 10.1016/j.canlet.2010.10.013. Epub 2010 Nov 13.
High-risk HPV E6 and E7 oncoproteins cooperate to subvert critical host cell cycle checkpoint control mechanisms in order to promote viral genome replication. This results not only in aberrant proliferation but also in host cellular changes that can promote genomic instability. The HPV-16 E7 oncoprotein was found to induce centrosome abnormalities thereby disrupting mitotic fidelity and increasing the risk for chromosome missegregation and aneuploidy. In addition, expression of the high-risk HPV E7 oncoprotein stimulates DNA replication stress as a potential source of DNA breakage and structural chromosomal instability. Proliferation of genomically unstable cells is sustained by several mechanisms including the accelerated degradation of claspin by HPV-16 E7 and the degradation of p53 by the high-risk HPV E6 oncoprotein. These results highlight the oncogenic potential of aberrant proliferation and opens new avenues for prevention of malignant progression, not only in HPV-associated cervical cancer but also in non-virally associated malignancies with disrupted cell cycle checkpoint control mechanisms.
高危型 HPV E6 和 E7 癌蛋白合作颠覆关键的宿主细胞周期检查点控制机制，以促进病毒基因组复制。这不仅导致异常增殖，还导致宿主细胞发生变化，从而促进基因组不稳定性。发现 HPV-16 E7 癌蛋白诱导中心体异常，从而破坏有丝分裂的保真度，并增加染色体错分和非整倍体的风险。此外，高危型 HPV E7 癌蛋白的表达刺激 DNA 复制应激，作为 DNA 断裂和结构染色体不稳定性的潜在来源。基因组不稳定细胞的增殖通过几种机制来维持，包括 HPV-16 E7 加速降解 claspin 和高危型 HPV E6 癌蛋白降解 p53。这些结果突出了异常增殖的致癌潜力，并为预防恶性进展开辟了新途径，不仅在 HPV 相关的宫颈癌中，而且在细胞周期检查点控制机制失调的非病毒相关恶性肿瘤中。
