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: 7393075
• 负责人: Dennis J. McCance
• 金额: $ 24.92万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393075
• 关键词: Affect; Aneuploid Cells; Aneuploidy; Barrett Esophagus; Bypass; Cancer Etiology; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cells; Chromosome abnormality; Chromosomes; Cytokinesis; DNA Damage; Epithelial Cells; Exhibits; Family; G2/M Arrest; G2/M Transition; Gene Expression; Genes; Genomic Instability; Head and Neck Cancer; Head and neck structure; Human; Human Papillomavirus; Human papillomavirus 16; Invasive; Lesion; Malignant Neoplasms; Microarray Analysis; Mitosis; Molecular Analysis; Numbers; Oncogene Deregulation; Papillomavirus; Pathway interactions; Pattern; Phase; Phase Transition; Play; Polyploidy; Premalignant; Premalignant Cell; Protein p53; Proteins; Retinoblastoma; Role; Role playing therapy; Signal Transduction; TP53 gene; Tissues; Up-Regulation; Viral Genes; Viral Proteins; Virus; cancer cell; keratinocyte; research study; tool

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入性癌症的标志，包括头部和颈部的癌症。浸润性癌细胞中染色体数量异常是由于细胞周期调节的损失，导致检查点和有丝分裂问题的损失。人乳头瘤病毒（HPV）在头颈癌的病因中起重要作用，我们已经表明，HPV 16型的E6和E7（通常与这些癌症相关的病毒），引起人类上皮细胞的多倍体/非整倍性。使用将表达E6和E7与对照细胞进行比较的上皮细胞的微阵列，我们发现了这些病毒蛋白对G2中的许多基因与M相跃迁。这些病毒基因引起染色体异常的事实表明，研究其作用机理，可能对其他非HPV诱导的癌症具有更大的影响。首先，我们建议确定在表达E6/ E7的细胞中受影响的有丝分裂/细胞因子的哪一部分。其次，研究肿瘤抑制剂，p53和视网膜母细胞瘤家族在G2/m转变中所起的作用。第三，确定特定的G2和M期基因如何被E6和E7激活，以及使用微阵列（如果HPV阳性和负头和颈部癌症之间存在不同的表达模式）。

项目成果

Regulation of epithelial differentiation and proliferation by the stroma: a role for the retinoblastoma protein.

• DOI: 10.1038/jid.2012.201
• 发表时间: 2012-12
• 期刊: JOURNAL OF INVESTIGATIVE DERMATOLOGY
• 影响因子: 6.5
• 作者: Pickard, Adam;Cichon, Ann-Christin;Menges, Craig;Patel, Daksha;McCance, Dennis J.
• 通讯作者: McCance, Dennis J.