Study of genomic instability caused by HPV16 E6 and E7

描述（由申请人提供）：基因组不稳定，导致多倍体/非整倍体细胞，是浸润性癌症（包括头颈部癌症）的标志。在侵袭性癌细胞中染色体数目异常的存在是由于细胞周期调控的丧失，导致检查点的丢失和有丝分裂的问题。人乳头瘤病毒（HPV）在头颈部癌症的病因学中起重要作用，并且我们已经表明，来自HPV 16型的E6和E7（一种通常与这些癌症相关的病毒）引起人上皮细胞中的多倍性/非整倍性。使用微阵列比较表达E6和E7的上皮细胞与对照细胞，我们发现了许多参与G2到M期转变的基因，这些基因被这些病毒蛋白解除调控。这些病毒基因导致染色体异常的事实表明，研究它们的作用机制可能对其他非HPV诱导的癌症具有更广泛的意义。我们建议，首先，以确定有丝分裂/胞质分裂的哪一部分是E6/E7表达细胞的影响。其次，研究肿瘤抑制因子p53和视网膜母细胞瘤家族在G2/M期转换中的作用。第三，确定E6和E7如何激活特定的G2和M期基因，并使用微阵列阐明HPV阳性和阴性头颈癌之间是否存在不同的表达模式。

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.