Study of genomic instability caused by HPV16 E6 and E7

HPV16 E6和E7引起的基因组不稳定性研究

• 批准号: 7183615
• 负责人: Dennis J. McCance
• 金额: $ 25.6万
• 依托单位: QUEEN'S UNIVERSITY BELFAST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7183615
• 关键词: Study; genomic; instability; caused; HPV16

DESCRIPTION (provided by applicant): Genomic instability, resulting in polyploid/ aneuploid cells, is a hallmark of invasive cancers, including those of the head and neck. The presence abnormal numbers of chromosomes in invasive cancer cells is due to loss of cell cycle regulation, resulting in lost of checkpoints and problems at mitosis. Human papillomaviruses (HPV) play a significant role in the etiological of head and neck cancers and we have shown that E6 and E7 from HPV type 16, a virus commonly associated with these cancers, cause polyploidy/ aneuploidy in human epithelial cells. Using microarrays comparing epithelial cells expressing E6 and E7 to control cells, we have found a number of genes involved in the G2 to M phase transition that are deregulated by these viral proteins. The fact that these viral genes cause chromosomal abnormalities suggests that studying their mechanisms of action, may have wider implications for other non-HPV induced cancers. We propose, firstly, to determine what part of mitosis/ cytokinesis is affected in E6/E7-expressing cells. Secondly, investigate the role played by the tumor suppressors, p53 and the retinoblastoma family in the control of G2/M transition. Thirdly, determine how specific G2 and M-phase genes are activated by E6 and E7 and fourthly elucidate, using microarrays, if there are different expression patterns between HPV positive and negative head and neck cancers.

描述（由申请人提供）：导致多倍体/非整倍体细胞的基因组不稳定性是侵袭性癌症（包括头颈部癌症）的标志。侵袭性癌细胞中染色体数量异常的原因是细胞周期调节丧失，导致检查点丢失和有丝分裂问题。人乳头瘤病毒 (HPV) 在头颈癌的病因学中发挥着重要作用，我们已经证明，HPV 16 型的 E6 和 E7（一种通常与这些癌症相关的病毒）会导致人上皮细胞的多倍体/非整倍体。使用微阵列比较表达 E6 和 E7 的上皮细胞与对照细胞，我们发现许多参与 G2 到 M 期转变的基因被这些病毒蛋白解除调节。这些病毒基因导致染色体异常的事实表明，研究其作用机制可能对其他非 HPV 诱发的癌症具有更广泛的影响。我们建议，首先，确定 E6/E7 表达细胞中有丝分裂/胞质分裂的哪一部分受到影响。其次，研究抑癌基因p53和视网膜母细胞瘤家族在G2/M转变控制中的作用。第三，确定特定的 G2 和 M 期基因如何被 E6 和 E7 激活，第四，使用微阵列阐明 HPV 阳性和阴性头颈癌之间是否存在不同的表达模式。