Oxidative DNA Damage, DNA Repair and Oral Cancer

DNA 氧化损伤、DNA 修复和口腔癌

• 批准号: 6643459
• 负责人: Chun-Yang Fan
• 金额: $ 13.37万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643459
• 关键词: DNA damage; DNA methylation; DNA repair; clinical research; gene mutation; genetic promoter element; human subject; immunocytochemistry; loss of heterozygosity; neoplasm /cancer genetics; oral pharyngeal neoplasm; oxidative stress; polymerase chain reaction; squamous cell carcinoma

DESCRIPTION (provided by applicant): Cigarette smoking is the major known head and neck cancer risk factor and represents the single leading preventable cause of death in the United States. Tobacco enhances the production of reactive oxygen species (ROS) in cells, resulting in the generation of oxidative lesions in DNA, such as strand breaks and oxidative DNA base lesions. Among various oxidative DNA lesions, 8-hydroxyguanine (8-OH-G) is by far the most abundant. If not sufficiently repaired, 8-OH-G can cause mutation by mispairing with adenine, yielding G:C to T:A transversion upon DNA replication. The human gene responsible for the repair of this specific DNA lesion was recently cloned and named human 8-oxoguanine DNA glycosylase (hOGG1). The hOGG1 gene is implicated in the carcinogenesis of head and neck squamous cell carcinoma (HNSCC) for several reasons. 1) The hOGG1 gene is located at 3p25, a chromosomal region with frequent allelic loss in HNSCC. 2) Yeast with mutations in this gene produce a mutator phenotype with accumulation of G:C to T:A transversions. 3) Studies of p53 mutations in HNSCC-related tumors showed a bias in favor of G:C to T:A transversions, as indeed would be expected if hOGG1 repair function was disabled. 4) The hOGG1 gene is amenable to the proposed study because of availability of its complete genomic DNA sequence, intragenic single nucleotide polymorphism (SNP) sites, and antibodies to the gene product. We hypothesize that hOGG1 inactivation promotes the development of oral SCC and this hypothesis will be tested by the following three specific aims. 1) Determine the frequency of loss of heterozygosity (LOH) in the hOGG1 gene. 2) Characterize the hOGG1 protein expression patterns in normal and neoplastic squamous mucosa. 3) Explore the genetic or epigenetic mechanisms of hOGG1 inactivation by identifying somatic mutations or promoter methylation in the oral SCC cases with evidence of LOH or lack of protein expression of hOGG1. The role of hOGG1 inactivation has never been previously examined in oral SCC. This study will help to determine whether hOGG1 can be used as a genetic marker for early detection, prognostic prediction, and a potential target for gene therapy in oral SCC. By obtaining a K award, the PI will have the opportunity to develop skills for patient- oriented research under the direction of basic and clinical science mentors.

描述(申请人提供)：吸烟是已知的主要职业 头颈部癌症的危险因素，代表了可预防的单一领先因素 在美国的死因。烟草提高了烟草的产量 细胞内的活性氧物种(ROS)，导致产生 DNA中的氧化损伤，如链断裂和DNA氧化碱基 损伤。在各种氧化性DNA损伤中，8-羟基鸟嘌呤(8-OH-G)是由 是最丰富的。如果没有得到足够的修复，8-羟基-G可能会导致 与腺嘌呤错配的突变，产生G：C到T：DNA的颠倒 复制。负责修复这种特定DNA的人类基因 新近克隆并命名为人8-氧鸟嘌呤DNA糖基酶 (HOGG1)。HOGG1基因与头颈部肿瘤的发生有关 鳞状细胞癌(HNSCC)的发生有多种原因。1)hOGG1基因为 位于HNSCC中的3p25，是HNSCC中等位基因丢失频繁的区域。 2)该基因突变的酵母产生突变子表型 G：C到T：A颠换的累积。3)P53基因突变的研究 与HNSCC相关的肿瘤表现出倾向于G：C到T：A的颠换， 如果hOGG1修复功能被禁用，确实是可以预期的。4)hOGG1 基因是服从于拟议的研究，因为它的完整 基因组DNA序列、基因内单核苷酸多态(SNP)位点、 以及针对该基因产物的抗体。我们假设hOGG1失活 促进口腔鳞癌的发展，这一假说将由 遵循三个具体目标。1)确定损失的频率 HOGG1基因杂合性(LOH)。2)鉴定hOGG1蛋白 正常鳞状黏膜和肿瘤鳞状黏膜的表达模式。3)探索 体细胞鉴定hOGG1失活的遗传或表观遗传机制 有杂合性缺失证据的口腔鳞癌病例中的突变或启动子甲基化 或hOGG1蛋白表达缺失。HOGG1失活的作用是 以前从未在口腔鳞癌中进行过检查。这项研究将有助于确定 HOGG1能否作为遗传标记进行早期检测、预后判断 预测，并成为口腔鳞癌基因治疗的潜在靶点。通过获得 K奖，PI将有机会为患者培养技能- 在基础和临床科学导师的指导下进行定向研究。